Chapter 2Pathophysiology and Evolutionary Aspects of Dietary Fats and Long-Chain Polyunsaturated Fatty Acids across the Life Cycle

Muskiet FAJ.

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Dietary fat is our second most important energy-producing macronutrient. It also contains fatty acids and vitamins essential for growth, development, and maintenance of good health. Dietary fat quantity and quality have been subject to tremendous change over the past 10,000 years. This has, together with other man-made changes in our environment, caused a conflict with our slowly adapting genome that is implicated in “typically Western” diseases. Rather than reducing our life expectancy, these diseases notably diminish our number of years in health. Important changes in dietary fat quality are the increased intakes of certain saturated fatty acids (SAFA) and linoleic acid (LA), introduction of industrially produced trans fatty acids, and reduced intakes of ω3 fatty acids, notably alpha-linolenic acid (ALA) from vegetable sources and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish. The pathophysiological effects of these changes are diverse, but are increasingly ascribed to induction of a proinflammatory state that progresses easily to chronic low-grade inflammation. The latter might affect virtually all organs and systems, possibly beginning at conception, and possibly even prior to gametogenesis through epigenetic alterations. Low-grade inflammation might be a common denominator of the metabolic syndrome and its sequelae (e.g., coronary artery disease (CAD), diabetes mellitus type 2, some types of cancer, and pregnancy complications), some psychiatric diseases (e.g., major and postpartum depression, schizophrenia, and autism), and neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease). The long-chain polyunsaturated fatty acids (LCPUFA) arachidonic acid (AA), EPA, and DHA are intimately related to the initiation and resolution of inflammatory responses. The current balance between AA and EPA + DHA is however disturbed by the dominance of AA, which originates from the diet or synthesis from LA. LCPUFA are together with their highly potent metabolites (prostaglandins, thromboxanes, leukotrienes, resolvins, and (neuro)protectins) involved in the functioning of membrane-bound receptors, transporters, ion channels, and enzymes, and also in signal transduction and gene expression. Among their many targets are nuclear receptors which, upon ligation with LCPUFA and their metabolites, function as transcription factors of a variety of genes functioning in many pathways. For instance, the targeted peroxisome proliferators-activated receptors (PPARs) are strategic intermediates in the coordinated expression of proteins with functions in, for example, lipid and glucose homeostasis and inflammatory reactions. Many interventions have been conducted with LCPUFA, especially EPA and DHA, aiming at primary and secondary CAD preventions, improvement of fetal and newborn (brain) development by supplementation during pregnancy or early postnatal life, and in psychiatric diseases. Consensus has been reached that those in CAD and depression are positive, although more large-scale trials are needed. Many recommendations for the intakes of saturated fat, trans fat and EPA + DHA have been issued, notably for CAD prevention, and also for EPA + DHA intakes by pregnant women and for AA, EPA, and DHA intakes by newborns. The ultimate goal might, however, be to return to the fat quality of our ancient diet on which our genes have evolved during the past million years of evolution, while this actually applies for our entire dietary composition and lifestyle, as translated to the culture of the current society.


Dietary fats and especially their caloric content and individual constituents, such as essential fatty acids (EFA) and fat-soluble vitamins, are indispensable for growth, development, and maintenance of good health. The nutritional value of dietary fats and their fatty acid composition cannot be considered in isolation since they are part of a diet that in its optimal form is balanced to fulfill the nutritional requirements of adults, and, in infants, children, and adolescents, should also be appropriate for growth and development. The corresponding nutrient needs, as defined by the Dietary Reference Intakes (DRIs) for both sexes and the various life stage groups, have been established by authoritative organizations such as the Food and Nutrition Board of the Institute of Medicine (DRI USA, 2008).

The influence of maternal diet prior to conception, during pregnancy and in early life on child development, and adult onset of many diseases is increasingly recognized (Gluckman et al., 2005). Many Nutritional Boards, for example that of The American Heart Association, recommend exclusive breastfeeding for 4–6 months, and, if possible, its continuation to 12 months, because of its beneficial effects on the prevention of obesity and its possible impact on lower blood pressure in later childhood, and on lower blood cholesterol at adult age. Some of these effects may be on the account of better self-regulation of energy intake and taste preference at later ages (Gidding et al., 2005). The period from weaning to a mature diet, usually from 4 to 6 months to 2 years, is characterized by the introduction of complementary foods* and should be guided by the physiologic and developmental readiness of the infant, nutrient requirements for growth and development, and other health considerations (Butte et al., 2004). Special emphasis is laid on the moderation of the consumption of “kid foods,” which tend to be high in fat and sugar, including excess juice, juice-based sweetened beverages, French fries, and nutrient-poor snacks, and may easily cause the exceeding of energy requirements. For those aged 2 years and older the emphasis is on a diet that primarily relies on fruits and vegetables, whole grains, low-fat and nonfat dairy products, beans, fish, and lean meat, which translates to low intakes of saturated fat, trans fat, cholesterol, and added sugar and salt, adequate intake of micronutrients, and an energy intake and physical activity appropriate to maintain a normal weight for height (Gidding et al., 2005).

After an introduction on the evolutionary aspects of our changing diet during the past 10,000 years and its relation with the development of “typically Western disease,” and stressing the importance of intrauterine and early postnatal diet, this chapter focuses on the influence of LCPUFA* on development, health, and disease.


Humans share a common ancestor with the chimpanzee and bonobo that probably lived in East Africa some 6 million years ago. Hominins have since then experienced a tremendous brain growth and assumed an upright position, which coincided with a change from a vegetarian to a hunting-gathering omnivore–carnivore. The oldest Homo sapiens found to date originates from the current Ethiopia and is about 160,000 years old (White et al., 2003). Since about 100,000 years ago humans have started to spread across the whole world to become the only Homo species currently inhabiting this planet. The “Out-of-Africa” Diaspora necessitated adaptation to new conditions of existence. Changes in physical characteristics gave rise to the concept of “race,” which is however better described by “geographical location” of origination as shown by studies of human genetic variation (Rosenberg et al., 2002). The number of new alleles that has been added to H. sapiens’ gene pool since the “Out-of Africa” Diaspora is small compared with the genetic variation that was already present in its founder population. If the total genetic variance is set at 100%, it becomes apparent that 93%–95% of the variance can be ascribed to differences between individuals belonging to a single population within a single race and that the differences between populations within a single race account for only 2%, so that the five races do not differ by more than 3%–5% (Rosenberg et al., 2002).

The vast majority of alleles that have been added to the already existing variance results from the selection pressure that was experienced by the changing environment since 160,000 years ago. They include alleles for protection against sunlight (skin (de)pigmentation, Jablonski and Chaplin, 2000; Harris and Meyer, 2006) and infectious diseases such as malaria (Cserti and Dzik, 2007), small pox, yellow fever, typhus, and cholera (Balter, 2005), and also for new diets such as milk consumption at adult age (lactase persistence, Harris and Meyer, 2006), gluten (grains, Cordain, 1999), and starch-rich diets (amylase copy number variation, Perry et al., 2007). The molecular clock hypothesis estimates that our nuclear DNA changes with an average rate of about 0.5% per million years (1.7 × 10−9 substitutions/site, year; Ingman et al., 2000). The genuine rate of genomic change is obviously dependent on the actual mutation rate, the magnitude of selection pressure, and other driving forces in population genetics, such as genetic drift (i.e., loss of genes in small populations). There is evidence that the rapidity became increased since the diminishing influence of famine and infection and the concomitant growth of the human population from some 40,000 years ago (Hawks et al., 2007), but basically we remained almost the same as the first H. sapiens, some 160,000 years ago. In other words, genetically, we are for the greater part still adapted to the East African ecosystem on which our genome evolved, with some adaptations since the Out-of-Africa Diaspora. It is clear that any change of environment is capable of introducing new selection pressure, with outcomes ranging from no effect to extinction, but also to an intermediate outcome that confers a loss of number of years in health without major influence on the chance to reach reproductive age. This basic principle of evolution was already noticed by Darwin in 1859.

2.2.1. Conflict between Current Diet and Our Ancient Genome

Since the agricultural revolution (i.e., some 10,000 years ago) we have gradually changed our diet and accelerated these changes from the beginning of the industrial revolution (100–200 years ago). The seven major dietary changes as recognized by Cordain et al. (2005) are summarized in Figure 2.1. Briefly, we have shifted our dietary macronutrient composition toward carbohydrates at the expense of protein, increased the intakes of ω6 fatty acids (notably LA from refined seed oils), SAFA and industrially produced trans fatty acids, decreased our ω3 fatty acid intake (both ALA and those from fish oil), shifted to a carbohydrate-rich diet that contains a high percentage refined carbohydrates with high glycemic indices (e.g., highly processed grains, sucrose, fructose), decreased the intake of certain micronutrients (e.g., folate, vitamin D, magnesium, zinc), shifted toward acid-producing foodstuffs (like meat, grains) at the expense of base-producing counterparts (fruits, vegetables), increased our sodium (salt) intake and reduced our potassium intake, and decreased the intake of fiber.

FIGURE 2.1. The seven crucial nutritional factors that have been changed since the agricultural and industrial revolutions.


The seven crucial nutritional factors that have been changed since the agricultural and industrial revolutions. (Data derived from Muskiet, F.A. et al., Prostag. Leukot. Essent. Fatty Acids, 75, 135, 2006. With permission.)

Table 2.1 compares the EFA intakes from the reconstructed Paleolithic diet with that of a typically Western diet and with current recommendations. Estimates of EFA intakes were calculated for a savanna-like diet (models 1 and 2, Eaton et al., 1998; Eaton and Eaton, 2000; Cordain et al., 2000) with different plant–animal subsistence ratios. In contrast to the savanna diet, the unpublished data of Kuipers et al. (models 3 and 4) assume a shore-based diet in which meat was mixed with fish harboring fatty acid compositions of those living in current Tanzanian lakes and the ocean (Kuipers et al., 2005, 2007). The median intakes (model 3) and their ranges (model 4), indicate that the mixing of fish into the savanna-like Paleolithic diet greatly increases the intakes of the sum of the fish oil fatty acids (EPA + DHA) to a median of 12.05 (range: 3.98–28.7 g/day), while the intakes of ALA and AA in all models are high, and that of LA is low. The calculated high LCPUFAω3 intakes compare well with those of the Eskimo’s who have lifetime high consumption of marine foods (see Section The models were constrained at a maximum intake of 35 en% from protein (Cordain et al., 2000), an intake of more than 1.7 en% LA to prevent biochemical signs of EFA deficiency (Barr et al., 1981) and an (EPA + DHA)/AA ratio above about 2.0. Low values for the latter ratio are related to CAD and neuroinflammatory diseases (Sections,,, and The (EPA + DHA)/AA constraint was calculated from the current recommended intake of 450 mg EPA + DHA/day, while the upper limit of the mean dietary intake of AA from typical Western diets is about 220 mg/day (Section, Astorg et al., 2004).



Estimated Intake of EFA from a Paleolithic Diet, as Compared with Intakes from a Current Typically Western Diet, RDAs, AIs, and AMDRs

The EFA and other changes in our diet together with an energy intake that does not match with our current sedentary lifestyle has caused a conflict with our genome that is likely to be at the basis of “typically Western” diseases. The resulting human phenotype centers around the metabolic syndrome,* which is a risk factor for associated diseases such as cardiovascular disease (CAD), diabetes mellitus type 2, osteoporosis, and certain types of cancer, notably those of the breast, prostate, and colon (Reaven, 2005; WCR/AICR, 2007). Many, if not all, of the polymorphisms that have been implicated in Western disease up to now give rise to perfectly normal genes that do not cause disease by themselves and are likely to have been with us since the first H. sapiens. With a generation time of 20–25 years, the nucleotide sequence of our genome could simply not have become adapted to these new conditions of existence. Polymorphisms giving rise to variant proteins with different sensitivities to dietary factors, such as vitamins (Ames et al., 2002), are widespread, and may cause a higher need in the homozygous and occasionally heterozygous states. If the prevalence of these genotypes exceeds 2.5% they are at least partially included into the recommended dietary allowance (RDA) for that dietary factor, which by definition equals the recommended intake for a certain nutrient that is sufficient for 97.5% of the population (Yates et al., 1998). Illustrative are homozygotes for the methylenetetrahydrofolate reductase 677 C → T (Ala222 → Val) allele and protein (MTHFR TT), which compared to MTHFR CT and CC counterparts, require higher folate status for optimal functioning of the variant enzyme. MTHFR TT has a prevalence of about 10%–20% in the white population, but is also widespread among the other races. Such polymorphic genes might better be referred to as “genes sensitive to faulty environment” (i.e., low folate), rather than “disease susceptibility genes.”

The domination of famine during human evolution has shaped our genome to what has been named the “thrifty genotype”* (Chakravarthy and Booth, 2004; Prentice et al., 2005) by Neel as early as 1962 (Neel, 1999). It is conceivable that basically, we are all carriers of the “thrifty genotype.” This hypothesis seems increasingly proven by genetic analyses, since the alleles with demonstrated risk of obesity in meta-analysis exhibit high frequency and confer low relative risk (Van den Berg, 2008), which might have been predicted from the evolutionary comprehensible phenomenon of high frequency–low penetrance and low frequency–high penetrance (Willett, 2002; The Wellcome Trust Case Control Consortium, 2007). It seems that our genetically determined “survival strategy” turns against us now that we can eat whatever we want and whenever we want, and need little physical activity for food procurement. This, so-called obesogenic environment has never existed in the past, was consequently not part of selection pressure, and genetic adaptations might therefore also not be expected. Consequently, obesity is not a genetic disease, apart from some rare mutations (Farooqi and O’Rahilly, 2006). The conclusion that it is “caused by an interaction between genes and environment” distracts from its causation by our current “faulty” environment and therefore does not carry useful information from a public health perspective. The identification of the underlying genes is nevertheless important from the point of view of health care, since it may help us target treatments in those who have developed disease from underexposure or overexposure to the underlying environmental factor(s).

2.2.2. Number of Years in Health

Fortunately, the current conflict between environment and our genome has not affected our Darwinian fitness* to an appreciable extent, since at present the majority of Western diseases occurs typically after reproductive age. We have on the contrary witnessed a tremendous increase of survival to reproductive age and of life expectancy, with a concomitant explosion of the world population. This achievement is however largely on account of the elimination of the aforementioned unfavorable conditions of existence, that is, notably through elimination of famine and infections (Eaton et al., 2002). Elimination of the meanwhile voluntarily introduced unfavorable environmental conditions and return to the dietary balance, and lifestyle in general, on which our genome has evolved, might restore “homeostasis,” increase the number of years in health, reduce the costs in healthcare, but not so much add to an increase of life expectancy (Eaton et al., 2002).


Intrauterine undernourished or malnourished, so-called programmed, newborns are at risk of some typically Western diseases at adult age, notably when they become exposed to the nutrient-rich postnatal environment and sedentary lifestyle that is characteristic for affluent societies and increasingly so for rapidly developing countries, that is, the “societies in transition” (Prentice and Moore, 2005). This “fetal origins” hypothesis of the early 1990s by Barker (1995, 2007) was initially based on the epidemiological relation between low birth weight and the development of CAD at adult age, but is now known to be associated with many diseases and their risk factors in affluent societies, such as obesity, diabetes mellitus type 2, stroke, osteoporosis, polycystic ovary syndrome, abnormal vascular compliance, endothelial dysfunction, insulin resistance, compromised hypothalamic–pituitary–adrenal (HPA) axis, and schizophrenia (Godfrey and Barker, 2000). More precisely, the hypothesis states that “limiting food resources at a vulnerable time during intrauterine growth and development may cause physical and metabolic adaptations of the fetus that predispose to disease in later life.” The hypothesis is also referred to as the “thrifty phenotype” and the “developmental origins of health and disease” (DOHaD) (Hales, 1997; Wells, 2003; Stocker et al., 2004; Prentice and Moore, 2005). It should, however, be noted that “low birth weight” is a proxy for intrauterine nutrient restriction, since “normal birth weight” does not preclude underdevelopment of particular organs or systems. Normal birth weight refers to quantity, not quality, and can, for example, still be attained if maternal nutrition is adequate in late gestation (Buckley et al., 2005). In addition, the hypothesis is nowadays not limited to the effects of undernourishment, since it has become clear that fetal overnutrition leading to “high birth weight” may exert similar effects (Cottrell and Ozanne, 2008). Such conditions are likely to become more prevalent, since “high birth weight” is clearly associated with disturbed maternal glucose homeostasis, such as occurring in diabetes mellitus type 2 and gestational diabetes.

2.3.1. Evolution and the Thrifty Phenotype

Low birth weight is usually derived from maternal malnutrition, undernutrition, placental dysfunction, or abnormal fetal handling (Godfrey and Barker, 2000). An overview of biological factors influencing prenatal growth and development is shown in Figure 2.2 (Ceelen et al., 2008). Dependent on type, timing, and duration, these insults may compromise growth of those organs developing in the affected time window or preclude the reach of the organism’s genetically determined maximum growth. Mechanistically, the ensuing growth restriction, and notably its hierarchy in terms of which organ becomes affected first, is likely to have an epigenetic* background aiming at adjusted development of the various organs and systems. Analogous to the “thrifty genotype,” the “thrifty phenotype” is also likely to find its origin in evolution. Dependent on the magnitude of the insult, these adaptations may either be of immediate value to survival (the so-called immediate adaptive response) or improve Darwinian fitness at a later stage of development (the so-called predicted adaptive response; PAR). They are to be distinguished from insults that cause gross pathology or even intrauterine death, such as the central nervous system pathology caused by severe iron, iodine, or folic acid deficiencies, of which the latter is known for its causal relation with neural tube defects. The immediate adaptive response comes with long-term costs in the sense of higher chance of disease development. The PAR is advantageous from an evolutionary point of view, because it allows for better adaptation to the predicted environment and thereby confers a higher chance of survival and reproductive success. Disease may, however, ensue if the predicted environment mismatches with the actual environment. The combination of the thrifty phenotype and a postnatal nutrition-rich environment, might constitute a not-readily observed mismatch between intrauterine and postnatal conditions in humans, that explains much of the epidemiology of Western disease (Bateson et al., 2004; Gluckman et al., 2005, 2007a; Gluckman and Hanson, 2006; Godfrey et al., 2007; Waterland and Michels, 2007; Hanson and Gluckman, 2008; Malina and Little, 2008).

FIGURE 2.2. Biological factors influencing prenatal growth and development.


Biological factors influencing prenatal growth and development. Effect sizes depend on the developmental stage (e.g., organogenesis, fetal period) of the conceptus. (Adapted from Ceelen, M. et al., Fertil. Steril., 90, 1662, 2008. With permission.)

2.3.2. The Thin Fat Baby

Many valuable data with regard to the thrifty phenotype have come from India. Comparison of the body compositions of a 2700 g newborn in India with a 3500 g newborn in the United Kingdom, revealed that the Indian baby has preserved brain volume, but has developed a relatively large adipose tissue compartment at the expense of muscle and visceral organs such as liver, pancreas, and kidneys (Figure 2.3) (Yajnik, 2004). The cord blood insulin and glucose levels of these “thin fat babies” are higher than those of counterparts born in the United Kingdom, while similar signs of insulin resistance are noticeable at the age of 4 and 8 years, especially when they grow fast (Yajnik, 2000). Interestingly, these differences in body composition seem to persist to adult age, since at similar body mass index, East Indians have higher percentage body fat, compared with Caucasians (Deurenberg et al., 1998; Yajnik and Yudkin, 2004). This fat mass is notably located in the abdominal cavity which is a feature of the metabolic syndrome in which low-grade inflammation, insulin resistance, and compensatory hyperinsulinemia are central (Reaven, 2005).

FIGURE 2.3. Body compositions of white Caucasian United Kingdom and East-Indian newborns.


Body compositions of white Caucasian United Kingdom and East-Indian newborns. The growth retarded Indian baby, also referred to as the “thin fat baby,” has preserved its brain volume and adipose tissue compartment at the expense of muscle (more...)

2.3.3. Animal Studies

Although the “fetal origins” hypothesis will remain unproven from randomized controlled trials (RCTs), it is well supported by animal studies (Buckley et al., 2005). Various intervention modes have been employed, including maternal nutrient restriction (e.g., protein, energy, iron), uterine artery ligation, and hormonal insults, such as glucocorticoid overexposure (Stocker et al., 2005). For instance, it was shown that the low birth weight offspring of undernourished pregnant mice develop obesity on a high-fat postnatal diet (Yura et al., 2005). Dietary protein restriction experiments in pregnant rats increases the susceptibility to insulin resistance and diabetes of their offspring if they receive a high-fat postnatal diet (Stocker et al., 2005). On a molecular basis, such experiments caused upregulated expression of genes for the glucocorticoid receptor (GR) and the PPAR-alpha in the offspring liver. These receptors are important to growth and development and have been implicated in the “fetal origins” hypothesis. Diminished methylation of their gene promoter regions was demonstrated to be at least one of the underlying mechanisms (Lillycrop et al., 2005). The state of hypomethylation of the PPAR-alpha gene promoter became conserved up to adult age (Lillycrop et al., 2008), but proved correctable by fortifying the protein-restricted diet with folic acid (Lillycrop et al., 2005). Importantly, these studies were the first to suggest a background of the fetal hypothesis in epigenetics. They demonstrate that the acquired epigenetic marks in utero may persist to adult age, while it becomes increasingly clear that these marks may also become transmitted to the next generation, giving rise to a seemingly genetic origin of the associated traits (Gluckman et al., 2007b).

Few studies have as yet been conducted to link the fetal origins hypothesis with dietary fat in pregnancy. One study in rats showed that a low fat intake in pregnancy retarded pulmonary maturation (Nelson et al., 1982). High fat intakes, especially those rich in SAFA and ω6 fatty acids, by pregnant animals caused similar effects on their offspring, when compared with administration after weaning. High SAFA intakes during pregnancy caused features of the metabolic syndrome in the offspring, including increased body fat, increased liver weight and triglyceride content, elevated circulating glucose and triglycerides, vascular dysfunction, permanent alterations in structure and function of the pancreas with faster and greater insulin responses upon a glucose challenge, severe endothelial dysfunction, hypertension, insulin resistance and secretory deficiency, and mitochondrial abnormalities that predispose to metabolic disease. Diets high in ω6 fatty acids caused disturbed glucose homeostasis and insulin responsiveness suggestive of insulin resistance, elevated body fat and abdominal fat at normal body weight, hepatic triglyceride accumulation, and downregulated expression of key-proteins in the insulin-signaling cascade (Buckley et al., 2005).

2.3.4. Decreasing Influence with Age

Consistent with the closure of the “window of opportunity” for the development of most organs, the influence of nutrition on reaching optimal organ cell numbers and subsequent development becomes less apparent and mechanistically less attributable to the thrifty phenotype per se with advancing age. The brain is a clear exception because of its growth up to about 2 years of age, with the time of delivery showing the highest growth rate. This rapid growth is also referred to as the “brain growth spurt” and in humans extends from the third trimester up to 18 months after birth (Innis, 1991). The chances of acquired mutations in the germ line and somatic cells obviously increase with advancing age, but the influence of environment also exerts cumulating effects on our epigenome, as elegantly demonstrated in a study of twins: it was shown that monozygous twins exhibit more epigenetic differences at older age, compared with infancy. This suggests that, dependent on environmental factors, our phenotype may progress in different directions with time and thereby explain part of the disease discordance in genetically identical twins (Fraga et al., 2005).

The identification of factors causing postnatal amplification and reversal of the metabolic adaptations of the thrifty phenotype is of crucial importance. Rapid post-natal growth is a well-studied risk factor, and it becomes increasingly clear that the stimulus of this growth and the ensuing obesity might largely be programmed in utero by altered leptin signaling (Cottrell and Ozanne, 2008). Importantly, it was recently shown in rats that some of the adverse effects associated with, dexamethasone-induced, low birth weight were offset by a postnatal diet rich in the fish oil fatty acids EPA and DHA. This treatment completely blocked the associated hyperleptinemia and hypertension, suggesting that fish oil fatty acids might prevent or at least reduce some of the adverse effects associated with low birth weight (Wyrwoll et al., 2006).


The influence of the postnatal diet on development of typically Western diseases has been studied intensively. Although fat and cholesterol consumption and high serum cholesterol have for long been blamed as the principal causes of the CAD epidemic, we now know that this so-called lipid–heart hypothesis” is at least incomplete and that dietary fat and cholesterol quantities hold questionable relations with CAD. There is no solid evidence that a high intake of fat per se is harmful in terms of CAD, cancer, or obesity in adults and also the influence of dietary cholesterol has been, and is still, exaggerated. For instance, consumption of one cholesterol-rich egg (about 200 mg/egg) daily up to six times per week does not increase risk of CAD or heart failure (Djousse and Gaziano, 2008a,b). The focus is nowadays mostly on fat quality (Lichtenstein, 2003) (see Section 2.4.2), while there is increasing evidence that carbohydrates, especially those with high glycemic indices, and food products with high glycemic loads play important roles in the etiology of obesity, insulin resistance, and CAD, and that a high protein intake reduces obesity risk (Last and Wilson, 2006). Food products with high glycemic loads, especially when consumed in isolation, cause transient hyperinsulinemia (which is associated with CAD) and postprandial hypoglycemia (which is associated with the stimulation of appetite) (Last and Wilson, 2006). Compared with three other diets the low-carbohydrate Atkins diet proved superior for weight loss within a 1 year RCT with overweight premenopausal women (Gardner et al., 2007). It was also shown that isoenergetic diets with high protein (25 en%) or monounsaturated fatty acids (MUFA; 21 en%) have more favorable effects on systolic blood pressure, serum lipid profile and CAD risk, when compared with a diet with 58 en% carbohydrates (Appel et al., 2005). Low-carbohydrate/high-protein diets have by now proven their favorable influence on weight loss (Last and Wilson, 2006), which however does not imply that all of these are healthy or easily maintained (Alhassan et al., 2008). It nevertheless gains acceptance that the for long propagated replacement of SAFA and trans fatty acids with an isoenergetic percentage carbohydrates has unfavorable effects on CAD risk. They might for this purpose better be replaced by unsaturated fatty acids (UFA), protein, or both. Also the messages that vegetable oils are “good” and animal fat is “bad” proved incorrect and so is the notion that all SAFA are “wrong” and that MUFA and polyunsaturated fatty acids (PUFA) are “right.” Categorizing fats into “tropical fats” and “nontropical fats” does not seem to make sense either. There are no “good” and “wrong” naturally occurring fats that have been part of our diet since the first H. sapiens, because nutrition is about the “balance” on which our genome has become to what it currently is.

2.4.1. Lipoproteins as Risk Factors

A high low-density lipoprotein (LDL)-cholesterol and low high-density lipoprotein (HDL)-cholesterol belong to the classical CAD risk factors that are nowadays, together with age, gender, systolic blood pressure, and smoking used for CAD risk assessment. The total-cholesterol/HDL-cholesterol ratio is the CAD risk factor most often applied in algorithms for CAD risk assessment, such as the SCORE, PROCAM, and Framingham algorithms (Graham, 2006). For instance, both the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) research group (PDAY Research Group, 1990) and the Bogalusa Heart Study (Berenson et al., 1998) indicated a positive relation of atherosclerotic lesions in postmortem aortas and coronary arteries of children, young adolescents, and young adults with serum total-cholesterol and LDL-cholesterol on the one hand and a negative relation with serum HDL-cholesterol on the other hand. Other classical CAD risk factors identified in these studies, and in which (dietary) fats may be involved, were obesity and blood pressure. The observation that a composite of PDAY risk factors, including HDL- and non-HDL-cholesterol, body mass index (BMI), and blood pressure, in 12–24 years children and adolescents predicted carotid artery intima-media thickness at ages 27–39 years (Graham, 2006) added to the notion that dietary fats may exert effects on classical CAD risk factors such as dyslipidemia and hypertension.

LDL-cholesterol lowering by statins has indeed proven to lower CAD risk in both primary and secondary prevention trials. These studies have shown that the lowest LDL-cholesterol confers lowest risk, and have set the stage for current treatment goals. Interestingly, the current LDL-treatment goals proved similar to LDL-levels encountered in traditionally living hunter-gatherer societies (O’Keefe and Cordain, 2004; O’Keefe et al., 2004). Statins however have pleiotrophic effects (Liao and Laufs, 2005) and their LDL-cholesterol lowering relates to a concomitant reduction of C-reactive protein (O’Keefe et al., 2006). Moreover, the pastoral living Maasai eating a saturated fat and cholesterol-rich diet (about 600 mg/day) from milk and meat have very low serum total-cholesterol, but extensive atherosclerosis with lipid infiltration and fibrous changes of their aortas, together with intimal thickening of their coronary arteries. They are however virtually free from signs of CAD, have smaller hearts, their blood pressure shows only a slight tendency to increase with age and they are remarkably fit (Mann et al., 1964, 1965, 1972). In addition, Central African Pygmies and Kalahari bushmen showed “prolonged hypoglycemia” after exogenous insulin and exhibited “low insulin responses” upon a glucose tolerance test (Joffe et al., 1971; Merimee et al., 1972). Taken together this suggests that the insulin sensitivity that comes with fitness and low BMI might be of crucial importance. With regard to lipids it might notably be of importance to prevent the production of small dense LDL- and HDL-particles that are associated with insulin resistance and part of the so-called atherogenic lipid triad, that is, elevated triglycerides, low HDL-cholesterol and small dense LDL particles (Krauss, 2004; Reaven, 2005).

2.4.2. Fat Quality as Risk Factor

It is widely accepted that atherosclerosis is associated with the consumption of SAFA and trans fatty acids by their ability to increase serum total- and LDL-cholesterol with no effect or decrease of HDL-cholesterol (Gidding et al., 2005). A detailed review on the effects of dietary fatty acids on serum cholesterol showed that isoenergetic replacement of 1 en% carbohydrates with SAFA, such as lauric acid (12:0*), myristic acid (14:0), and palmitic acid (16:0) increases LDL-cholesterol, but also HDL-cholesterol (Mensink et al., 2003). Stearic acid (18:0) does not influence LDL- and HDL-cholesterol to an appreciable extent. However, lauric acid induces a significant decrease of the total-cholesterol/HDL-cholesterol ratio, which implies that replacement of carbohydrate with the saturated 12:0 lowers CAD risk from at least a theoretical point of view. Replacement of 1 en% carbohydrates with SAFA, cis-MUFA, PUFA, or trans-MUFA does not induce much change in the total-cholesterol/HDL-cholesterol ratio for SAFA, causes a steep decrease for cis-MUFA and PUFA, but produces an increase for trans-MUFA. Replacement of 10 en% of the typical U.S. diet with carbohydrates or a variety of naturally occurring fats or oils would theoretically cause the steepest increase of the total-cholesterol/HDL-cholesterol ratio for carbohydrates and the steepest decrease of this ratio for rapeseed oil, soybean oil, and olive oil (Figure 2.4; Mensink et al., 2003). Taken together, these data suggest favorable effects of reduced carbohydrate consumption and are illustrative for the nuance with regard to the influence of naturally occurring fatty acids, fats, and oils on our serum lipid risk profile. In addition, EPA and DHA have little effects on serum cholesterol, apart from a modest increase of LDL-cholesterol. Their favorable effects on CAD risk are attributed to their antiarrhythmic, antithrombotic, antiatherosclerotic, and anti-inflammatory effects, while they improve endothelial function, and lower both blood pressure and serum triglycerides (Din et al., 2004; Lee et al., 2008; Mozaffarian, 2008).

FIGURE 2.4. Predicted changes in serum total-cholesterol/HDL-cholesterol ratio if a mixed fat constituting 10% of energy in the “average” U.


Predicted changes in serum total-cholesterol/HDL-cholesterol ratio if a mixed fat constituting 10% of energy in the “average” U.S. diet is isoenergetically replaced by carbohydrates or various fats and oils. (Adapted from Mensink, R.P. (more...)

It has become clear that the dietary fatty acid composition may not only adversely affect serum cholesterol, but also influences coagulation, endothelial function, inflammation, abdominal obesity, insulin sensitivity, development of type 2 diabetes mellitus, and arrhythmias (Erkkila et al., 2008). Such adverse conditions are likely to have been introduced by the increasing intake of SAFA, trans fatty acids and ω6 fatty acids (notably LA) in the Western diet during the past century and the concomitant decrease of the ω3 fatty acids intake from vegetable oils and fish (Figure 2.5; Simopoulos, 1999, 2006). A diet-induced proinflammatory and prothrombotic state may be part of the chronic low-grade systemic inflammation that is associated with the insulin resistance and compensatory hyperinsulinemia of the metabolic syndrome (Reaven, 2005). The current dominance of the ω6 fatty acid series (LA and AA) over those from the ω3 series (ALA, EPA, and DHA) may at least partially be at the basis of this proinflammatory and prothrombotic state (Innis, 2007b; Siddiqui et al., 2008). Low-grade inflammation is emerging as a common feature of the metabolic syndrome (Tilg et al., 1994) and its sequelae, but also of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis (Skaper, 2008), and also major depression (Leonard, 2007) (see Section The relation with disbalanced ω6/ω3 ratio might find its origin in ω6-mediated aggravation of inflammatory responses in conjunction with insuffficient ω3-mediated compensatory anti-inflammatory responses. Recent research indicates that the inflammation initiation/resolving balance is orchestrated by the proinflammatory actions of prostaglandins and leukotrienes from AA, and the inflammation-resolving actions of the lipoxins from AA, and the resolvins and (neuro)protectins from EPA and DHA (Calder, 2006; Mayer and Seeger, 2008; Serhan et al., 2008). Evidence from both observational and experimental studies indicates that industrially produced trans fatty acids, notably those from LA, may also be proinflammatory by as yet are poorly understood mechanisms (Mozaffarian and Willett, 2007). Other adverse effects of trans fatty acids include a decrease of incorporation of other fatty acids in cell membranes, decrease of HDL-cholesterol and increase of LDL-cholesterol, fatty acid desaturase 2 (FADS2) inhibition, decrease of testosterone, lowering of birth weight, increases of platelet aggregation, lipoprotein (a), body weight, and cholesterol ester-transfer protein, and abnormal morphology of sperm (Simopoulos, 2008).

FIGURE 2.5. Fat intake of hominins and H.


Fat intake of hominins and H. sapiens since our common ancestory with the current chimpanzee. Inlays: Reconstruction of H. sapiens Idaltu dated about 160,000 years ago (White et al., 2003), central obesity as a characteristic of the metabolic syndrome, (more...)

2.4.3. Prospective Studies, Trials, and Recommendations

The risk of the type of fat has been reasonably well established, notably for CAD development. There are obviously no population-based RCTs for primary prevention with hard endpoints, which makes it difficult to establish the causality of the relation of dietary fat quality with diseases like CAD. A recent review on prospective cohort studies and trials with hard endpoints concluded that SAFA and industrially produced trans fatty acids increased CAD risk in several studies, while both ω6 (notably LA) and ω3-PUFA are associated with lower CAD risk. From the ω3 fatty acids, both EPA and DHA are associated with decreased risk for especially fatal CAD outcomes, while the role of ALA is less clear (Erkkila et al., 2008; Stark et al., 2008). There are few studies with children and all of those available carry soft endpoints. Reduction of elevated LDL-cholesterol in 8–10 years old children was accomplished by the consumption of a low-fat diet with reduced SAFA and cholesterol (Obarzanek et al., 2001). Repeated dietary counseling to lower SAFA and cholesterol intake from 7 months, as monitored up to 14 years of age, has recently been found effective in lowering total- and LDL-cholesterol, notably in boys, without affecting growth, BMI, pubertal development, and age of menarche (Niinikoski et al., 2007). A high intake of fish oil fatty acids is epidemiologically associated with reduced CAD risk, while a low intake has been associated with depression. Favorable effects of fish oil on hard CAD endpoints have clearly been demonstrated in secondary prevention studies (Lee et al., 2008). Favorable effects of EPA on depression have been shown in RCTs, although more data are needed (Ross, 2007) (see Section 2.5.4).

The current (2005) acceptable macronutrient distribution range (AMDR) issued by the U.S. Institute of Medicine for fat intake by adults (>18 years) amounts to 20–35 en% and, dependent on age group, amounts to 14–17 g/day ω6-PUFA (LA) for men and 11–12 g/day for women (5–10 en%), and to 1.6 g/day ω3-PUFA (ALA) for men and 1.1 g/day for women (0.6–1.2 en%). About 10% of total PUFA may come from LCPω3 or LCPω6. Since it is contended that there is an increase in plasma total- and LDL-cholesterol with increased intake of SAFA or trans fatty acids or with cholesterol at even very low levels in the diet, it is recommended that the intakes of each should be minimized while consuming a nutritionally adequate diet (DRI USA, 2008). The current (2006) adequate intakes (AIs) in the Netherlands are: 20–40 en% fat (tolerable upper intake level; UL 40 en%), as low as possible SAFA (UL < 10 en%) and trans-MUFA (UL < 1 en%), PUFA (UL = 12 en%), MUFA + PUFA 8–38 en%, LA 2 en% for prevention of EFA deficiency, ALA 1 en% and EPA + DHA 450 mg/day (Health Council of the Netherlands, 2006). Recommendations for fish oil fatty acid intake for primary prevention have been issued by authoritative Nutritional Boards ranging from “choose fish as food item more often” to two to three servings of fish per week (Psota et al., 2006). For secondary prevention the American Heart Association recommends 1 g EPA + DHA daily, preferably from fatty fish or otherwise from fish oil supplements, while 2–4 g daily is recommended for serum triglyceride lowering (Kris-Etherton et al., 2002). The currently advised intake of about 450 mg LCPω3/day confers virtually maximum antiarrhythmic effects, but is below the estimated dosage that confers maximum benefits for other CAD risk factors responding favorably to fish oil (Mozaffarian, 2008). A recent study from Belgium showed that at the recommended consumption of 0.3 en% EPA + DHA (i.e., about two times fatty fish/week) the intake of methyl mercury remains well within the tolerable daily intake, but that the dioxin-like compounds approach the current limit at more than two times fatty fish per week (Sioen et al., 2007). The benefits of two seafood servings per week exceed the potential risk, notably when a variety of fish is chosen and the consumption of species with high contaminant levels is avoided (Mozaffarian and Rimm, 2006).


There is good evidence to show that the evolution to H. sapiens took place on an ω3-rich diet from East-African ecosystems that were notably located in places where the land meets freshwater. The sites at which the fossil remains of our ancestors have been discovered are in support of this notion (Gibbons, 2002b), while the Out-of-Africa Diaspora has largely taken place via the coastal lines (Stringer, 2000) also after the crossing of the Bering Strait (Wang et al., 2007). Compared with hunting in the savanna, food from the land–water ecosystems is relatively easy to obtain and rich in iodine, vitamins A and D, and ω3 fatty acids from both vegetables and fish. Each of these nutrients has important functions in brain development and growth. Exploitation of this ecosystem, and its abundant “brain food,” might be at the basis of our remarkable brain growth during the past 6 million years of evolution since our common ancestry with the present chimpanzee. This dietary composition seems somewhat abandoned since the Out-of-Africa Diaspora, since deficiencies of many of these particular nutrients are among the most widely encountered in the current world population (Broadhurst et al., 1998, 2002; Crawford et al., 2001; Holick and Chen, 2008). Iodine is added to table salt in many countries, and margarines and milk have become popular food products for fortification with vitamins A and D. The dietary composition of our ancestors has also become clear from our current (patho)physiology: epidemiological data demonstrated a negative association of fish consumption with CAD (see Section 2.4) and (postpartum) depression (Hibbeln, 1998, 2002), while landmark trials with ALA (de Lorgeril et al., 1999) and fish oil (GISSI-Prevenzione trial, 1999; Lee et al., 2008) in CAD, and with EPA in depression and schizophrenia (Peet and Stokes, 2005) supported the causality of these relations. It has become clear that the intake of the parent EFA and their chain elongation/desaturation metabolites, the so-called LCPUFA (≥20 straight-chain carbon atoms and ≥3 methylene-interrupted cis-double bonds) is important to our health across the entire life cycle, but that their intakes have been subject to tremendous change. This section deals with their (patho)biochemistry and (patho) physiology and specifically concentrates on their role in pregnancy, neonatal nutrition, and psychiatric disease.

2.5.1. (Patho)biochemistry and Physiology of LCPUFA LCPUFA Synthesis, Regulation, and ω3/ω6 Balance

LA (18:2ω6, precursor of the ω6-series fatty acids) and ALA (18:3ω3, precursor of the ω3-series) are the parent EFA for humans (Innis, 1991, 2003). “Essential” implies that the nutrient in question cannot be synthesized to sufficient amounts and therefore needs to be obtained from the diet to prevent development of disease. Most of the dietary LA and ALA is used for energy generation, converted to other compounds or used for structural purposes. Especially LA can become stored to reach high levels in adipose tissue. The parent EFA are also converted to LCPUFA by microsomal desaturation (delta-6 and delta-5 desaturases; also referred to as FADS2 and fatty acid desaturase 1 (FADS1), respectively), microsomal chain elongation, and peroxisomal chain shortening (Figure 2.6). Humans do not possess a delta-4 desaturase, which precludes the direct synthesis of DHA from its precursor 22:5ω3. Direct desaturation is circumvented by initial elongation of 22:5ω3 to 24:5ω3, followed by delta-6 desaturation by FADS2 and a single cycle of beta-oxidation in peroxisomes to yield DHA. The output of this pathway is, however, limited (Muskiet et al., 2004; Burdge, 2006; Williams and Burdge, 2006) as may, for example, be derived from the lower DHA status of vegans compared with omnivores (Fokkema et al., 2000a), and the inability to augment DHA status by supplementation with ALA (Fokkema et al., 2000b) or very high EPA (Horrobin et al., 2003). Supplemental ALA does however increase EPA and 22:5ω3 status (Stark et al., 2008).

FIGURE 2.6. Chain elongation and desaturation pathways of the parent essential fatty acids ALA and LA, and of stearic and palmitic acids.


Chain elongation and desaturation pathways of the parent essential fatty acids ALA and LA, and of stearic and palmitic acids. Abbreviations: ALA, alpha-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GLA, gamma-linolenic acid; DGLA, (more...)

The sharing of the elongating and desaturating enzymes by ω6 and ω3 fatty acids causes them to compete for conversion into the various LCPUFA. It must however be appreciated that the ω3 and ω6 fatty acids also compete in many other pathways, such as beta-oxidation, incorporation into lipids, release from lipids, conversion into highly active metabolites, and binding to receptors. Circulating AA levels are relatively constant at LA intakes ranging from 3 to 10 en% (Innis, 2007b). Consumption of a high LA diet by healthy adults increases plasma phospholipid LA and decreases EPA with no effect on AA (Liou et al., 2007), suggesting that our current high LA intake contributes to our low EPA/AA ratio. Generally, high EPA and DHA intakes lower AA status in some tissues, erythrocytes (RBC), and circulating lipids (Innis, 2003), but this does not seem to occur to the same extent in all compartments, notably not in the brain. For instance at variable DHA status, DHA and 22:5ω6 exhibit inverse relationships in rat frontal cortex, with little effect on AA (McNamara and Carlson, 2006). AA in the postnatal baboon central nervous system (CNS) seems tightly controlled and much less sensitive to dietary manipulation than DHA, possibly because the pathway for AA synthesis from the abundant LA (by three endoplasmic steps) might be more efficient than the pathway of DHA from the less abundant ALA (by six endoplasmic and one peroxisomal step). Postnatal feeding with formulae without DHA causes a DHA drop in most CNS structures of the baboon infant, which can be prevented by alternative feeding with a formula with DHA (Diau et al., 2005; Brenna and Diau, 2007). Brain LCPUFA profiles exhibit remarkable similarity among different mammals (Tassoni et al., 2008) and the data on the DHA vs. AA relation in animal brain are in line with the limited cross-sectional data from the brains of young infants. These show lower DHA and somewhat higher (Farquharson et al., 1992) or equal (Makrides et al., 1994) AA in children who received infant formula without LCPUFA, compared with counterparts receiving breastmilk (which contains LCPUFA). Nevertheless, the complex interrelationships between the two EFA series puts emphasis on the need of dietary “ω6/ω3 balance” to reach “homeostasis.” The dietary composition producing this “balance” is as yet unknown, but it may be postulated that it is part of our ancient diet, because it is that diet on which our genes evolved.

The regulation of LCPUFA synthesis is complex and notably targets FADS1 and FADS2. Both enzymes are widely expressed in human tissues, notably in liver (Nakamura and Nara, 2004), but also in the brain, placenta, and the mammary gland (Innis, 2005, 2007a,c). The liver enzymes seem major origins of the LCPUFA synthesized from LA and ALA. The contributions of the brain, placenta, and mammary gland enzymes to brain, fetal, and newborn LCPUFA status are uncertain but probably small. For instance, DHA synthesis in the adult rat liver is sufficient to keep brain DHA constant while the brain itself is unable to do so (Rapoport et al., 2007). There are no differences in the capacities to convert ALA to DHA between prematures, term babies, and adults (Innis, 2007a). Women have higher capacity to synthesize DHA, which might be mediated by estrogens (Williams and Burdge, 2006). Compared with LCPUFA synthesized from their parent precursors, there is a clear preference for preformed AA and DHA from the diet for incorporation into brain and other tissues (Lin and Su, 2007; DeMar, Jr. et al., 2008) and for preformed DHA originating from transplacental transfer and milk for fetal and newborn tissue accretion (Innis, 2005). Dietary LCPUFA downregulate LCPUFA synthesis by negative feedback inhibition (Nakamura and Nara, 2004). Insulin stimulates the expression of both enzymes, while it also stimulates expression of delta-9 desaturase (steroyl-CoA desaturase) (Brenner, 2003; Jump, 2004). The latter is the third important desaturase that is notably related to de novo fatty acid synthesis and is, for example, induced in adipose tissue during insulin resistance (Sjogren et al., 2008). Other factors affecting LCPUFA synthesis are various hormones, cofactors like vitamin B6 and zinc, and inflammatory stimuli (Nakamura and Nara, 2003; Jump, 2004). Downregulation of LCPUFA synthesis by dietary LCPUFA, the presumed high LCPUFA intakes from our ancient diet (Table 2.1), the occurrence of FADS1 and FADS2 polymorphisms with lower activities (see Section, and our difficulty to synthesize DHA suggest that the LCPUFA synthesis machinery has only been used during long periods with low LCPUFA intakes, such as during famine or limited availability of animal foods. The low AA level and higher ratio between dihomo-gamma-linolenic acid and AA (DGLA/AA) in plasma phospholipids of Greenland and Danish Eskimos, compared with Danes, has led to the suggestion that Eskimos may have low FADS1 activity. This would render them obligate carnivores who, similar to cats, are in need of a dietary LCPUFA source (Gibson and Sinclair, 1981).

The FADS1 and FADS2 genes are located in a head-to-head orientation on chromosome 11. The proximity of their promoters suggests that they might be coordinately controlled by common regulatory sequences but this has not been demonstrated as yet. The FADS2 promoter contains binding sites for the (ligated) PPAR-alpha (see Section and the active form of the sterol regulatory-binding protein-1c (SREBP1c). Binding of the ligated PPAR-alpha and SREBP-1c proved necessary for FADS2 transcription and this was found to occur notably during LCPUFA demand, such as in EFA deficiency. Consequently, PPAR-alpha and SREBP-1c may collectively be considered as our “LCPUFA sensors” (Nakamura and Nara, 2004). The strong feedback control on LCPUFA synthesis by LCPUFA is mediated by reduced FADS2 transcription secondary to the reduction of the active form of SREBP-1c. This mode of regulation implies that excess of dietary LCPUFA from either the ω3 or ω6 series may shut off synthesis of both LCPUFA series, which is a strong argument for the need of dietary LCPω3/LCPω6 balance, and may play a role in the AA lowering effect of DHA supplementation (Nakamura and Nara, 2004). Transcription of the opposite strand of FADS1, named reverse-FADS1, gives rise to an antisense transcript that is able to bind to complementary sequences of the FADS1 transcript and thereby lowers or even switches off FADS1 translation. Fasting and refeeding with a high glucose fat-free diet and administration of fish oil were found to be triggers for the induction of the antisense regulator of FADS1, which probably exerts its action by accelerating FADS1 mRNA degradation or interference with its translation (Dreesen et al., 2006). One-carbon metabolism is linked to LCPUFA metabolism and status by the methylation of phosphatidylethanolamine (PE) to phosphatidyl-choline (PC) via the phosphatidylethanolamine-N-methyltransferase (PEMT) pathway (Watkins et al., 2003; Umhau et al., 2006). PC may also become synthesized via the CDP-choline pathway, but the resulting species carry less AA and DHA than those deriving from the PEMT pathway. In addition, hyperhomocysteinemia was recently shown to influence LCPUFA synthesis by the silencing of FADS2 in mouse liver. The mechanism was by hypermethylation of the FADS2 promoter and was accompanied by higher PE, and lower AA and DHA in liver phospholipids (Devlin et al., 2007). Dietary LCPUFA Sources and Intakes

Both LA and ALA are predominantly derived from vegetable oils. The various edible oils differ widely in LA and ALA contents and their ratio. Sunflower oil and corn oil are, for example, high in LA, and soy bean oil and especially linseed oil have (much) higher ALA/LA ratio. Meat, eggs, and poultry are rich sources of AA, while EPA and DHA are derived notably from fish, meat, and eggs. The EPA and DHA contents and ratios in fish are dependent on their position in the food chain and the composition of the phytoplankton from which these LCPω3 ultimately originate. Freshwater fish may synthesize their own EPA and DHA from the appropriate precursors (Sargent, 1997). There are little differences in reported intakes of LA in Western countries, which are typically in the 11–18 g/day range. Also AA intake is rather constant, amounting to 160–230 mg/day for men and 120–200 mg/day for women. This may, together with the constancy of AA across a wide range of LA intakes (3–10 en%), explain the constancy of AA status in Western countries (Liou et al., 2007; Innis, 2007b). In contrast, there are wide differences in ω3 fatty acid intakes and the resulting ω3-status. ALA intake in Western countries is typically 1.2–1.8 g/day, but is up to 1.7–2.2 g/day in Japan. The LA/ALA ratio amounts to 4–8 in Japan, 6–10 in most Western countries, and >13 in South-European countries (Astorg et al., 2004), but has also been estimated at 15–16 for the typical Western diet (Simopoulos, 2001). Notably LCPω3 intake is highly variable among countries. EPA + DHA intakes in Japan are 1.0–1.5 g/day for men and 0.7–1.1 g/day for women. They amount to 0.7–1.0 g/day in Norway and 0.7 g/day in Spain, while relatively low intakes have been reported for the United States (210–240 mg/day), Germany (215–315 mg/day), and Australia (175 mg/day) (Astorg et al., 2004). Vegetarians consume 30 mg DHA/day (Haggarty, 2004). Lifetime LCPω3 intakes by Eskimos has been estimated at 14 g/day, while the intake in Denmark was 3 g/day (Feskens and Kromhout, 1993). The latter figures compare favorably with our estimates for an East-African freshwater-based diet of our ancestors (see Table 2.1). Higher LCPω3 intakes than the 450 mg/day as currently advised would not only provide maximal effects on arrhythmia risk, but also on the lowering of serum triglycerides, heart rate and blood pressure, and on thrombosis risk (Mozaffarian, 2008). Docosapentaenoic acid (22:5ω3) intake seems to occur notably from meat, with total daily intakes of 85–105 mg in Japan, 60–80 mg in Sweden and France, and 71 mg in Australia (Astorg et al., 2004; Howe et al., 2006). Gamma-linolenic acid (GLA) is abundant in borage, black current, and evening primrose oils (Kapoor and Huang, 2006). EFA and LCPUFA Function

The parent EFA (notably LA) and LCPUFA are building blocks of the membrane phospholipids of all cells. They contribute to the membrane’s physicochemical properties and thereby the functions of membrane-bound receptors, transporters, ion channels, enzymes, and other membrane-bound biochemical processes, such as those involved in signaling pathways. LA has a clear structural function of its own. As building block of ceramides in our skin, LA contributes to the skin’s barrier function to limit transepidermal water loss. In contrast to LA, ALA gets stored in our body to only a limited extent. ALA is largely degraded to acetyl-CoA for the generation of energy or de novo synthesis of SAFA, MUFA, and cholesterol, for example, in the brains of the fetus and newborn (“recycling,” Cunnane et al., 2006). LA and LCPUFA are also stored in adipose tissue, but especially AA exhibits preference for phospholipids (Nelson et al., 1997) perhaps to control AA release and subsequent conversion to its highly potent eicosanoids. EFA make up 20% of brain dry weight, including about 6% for AA and 8% for DHA. Brain levels of LA and ALA are low. DHA and AA are notably located in the synaptosomes, where AA is of special importance as a second messenger in (synaptic) signal transduction and DHA provides the needed fluidity for appropriate neurotransmitter receptor activity. DHA is the major fatty acid in the structural phospholipids of the retinal photoreceptor outer segment membrane, where its fluidity is essential to accommodate the extremely rapid conformational changes of rhodopsin (Kurlak and Stephenson, 1999). Part of the retinal phospholipids is composed of PE, phosphatidylserine (PS), and PC that carry two DHA acyl moieties. Brain AA and DHA reach highest levels in gray matter and especially those areas involved in motor activities (Diau et al., 2005). DHA’s role in neurodevelopment has been grouped into effects on gene expression, mono-aminergic neurotransmission, protection against apoptotic cell death, and neurite outgrowth from the cell body (Innis, 2007a). DHA also has an important function in spermatozoa, where DHA’s unique structure contributes to motility (Tavilani et al., 2006). Both AA and DHA are important to maintain a healthy endothelium of our cardiovascular system (Calder, 2004). The importance of AA/DHA balance in myocardial phospholipids to preserve a low arrhythmogenic eicosanoid profile has been emphasized (McLennan and Abeywardena, 2005). LCPUFA synthesis from parent precursors may also be subject to “programming” (see Section 2.3). A diet high in SAFA given to pregnant rats caused reduced AA and DHA and increased LA and ALA in the aorta of their offspring, suggesting poor conversion of parent EFA to LCPUFA. These abnormalities coincided with vascular dysfunction and persisted to adulthood (Ghosh et al., 2001). Eicosanoids, Resolvins, Protectins, and Others

LCPUFA are precursors of highly potent metabolites that are involved in various signaling processes. After their release from membrane phospholipids by phospholipase A2 (PLA2) some of the C20 LCPUFA, that is, AA (20:4ω6), DGLA (20:3ω6), and EPA (20:5ω3) may become converted to eicosanoids (prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids, and epoxy-eicosatrienoic acid), which is a family of lipid mediators synthesized via the cyclooxygenase (COX1 and COX2), lipooxygenase (LOX), and the cytochrome P450 pathways. DGLA gives rise to prostaglandins, prostacyclins, and thromboxanes of the one-series (e.g., PGD1, E1, F), AA leads to the two-series (PGD2, E2, F, PGI2, TXA2) and EPA to the three-series (PGD3, E3, F, PGI3, TXA3). AA is also converted to the four-series leukotrienes (LTA4, B4, C4, D4), while EPA gives rise to the five-series leukotrienes (LTA5, B5, C5, D5). These mediators are involved in a variety of occasionally opposing functions such as smooth muscle contraction, fever induction, augmentation of vascular permeability, pain, vasodilation (PGE2), vasoconstriction and platelet aggregation (TXA2), vasodilation and platelet aggregation inhibition (PGI2), contraction of smooth muscles in the respiratory tract, vessels, and intestine, leukocyte chemotaxis, increased vascular permeability, enhanced local blood flow, and release of lysosomal enzymes and reactive oxygen species (LTB4) (Calder, 2006).

The eicosanoids from EPA are believed to be less potent than those of AA. For instance, TXA3 is a weak agonist of TXA2 in inducing vasoconstriction and platelet aggregation, while PGI2 and PGI3 exert similar vasodilating and antiaggregating effects. Also LTB5 is much less potent in eliciting neutrophil chemotaxis than LTB4. Eicosanoids from AA are widely considered to be proinflammatory, whereas those from EPA are weakly inflammatory or anti-inflammatory. This must however be viewed upon as a generalization, since newly identified mediators of AA are not only involved in the initiation, but also in the resolution of inflammatory reactions. Prostaglandins and leukotrienes are intimately involved in the initiation of inflammation following its triggering by, for example, microbial infection, surgical trauma, hypoxia, and reperfusion injury. The outcome is progression to chronic inflammation, scarring and fibrosis, or complete resolution. Resolution is accompanied by a switch to the production of lipid mediators with anti-inflammatory and proresolving properties. These mediators include AA-derived lipoxins, which function as stop signals and are followed by the appearance of EPA-derived resolvins from the E-series and DHA-derived resolvins from the D-series and protectins (named neuroprotectins when generated in the neural tissue). Mediators from EPA and DHA stimulate resolution and the return to homeostasis (Serhan et al., 2008; Serhan and Chiang, 2008). LCPUFA and Gene Expression

LCPUFA are not only important structural elements of membranes. Together with their eicosanoid products and other fatty acids, they are also firmly implicated in gene expression. For example, dietary LCPUFA are ligands of PPARs and suppress the expression of SREBPs, nuclear transcription factor kappa-B and others. These are nuclear transcription factors that can be considered as main switches in the coordinated expression and repression of a variety of (key) enzymes and proteins in intermediary metabolism, thermoregulation, energy partitioning, growth and differentiation, and inflammatory responses (Duplus and Forest, 2002; Clarke, 2004; Jump, 2004; Lapillonne et al., 2004). PPARs are among our bodily “lipid sensors” and, importantly, they constitute a link between lipid and glucose homeostasis, and inflammation (Figure 2.7). The serum triglyceride lowering effect of fish oil fatty acids is, for example, attributable to their interaction with PPAR-alpha. Recent data show that DHA and EPA play key regulatory roles in the coordinated expression of genes involved in glycolysis, de novo lipogenesis, fatty acid elongation, desaturation, and oxidation in the liver. They target many nuclear receptors that are part of at least three major transcriptional regulatory networks controlling hepatic carbohydrate and lipid metabolism, that is, by activation via the PPARs/retinoid X receptor (RXR) heterodimer and suppression of the nuclear abundances of SREBP-1 and the carbohydrate regulatory element-binding protein (ChREBP)/Max-like factor X (MLX) heterodimer. DHA weakly activates PPAR-alpha and strongly suppresses SREBP-1, while its hepatic retroconversion metabolite EPA is a strong PPAR-alpha activator. PUFA of both the ω3- and ω6-series suppress ChREBP/MLX abundance (Jump, 2008). Because of their strategic role in many metabolic and signaling routes PPARs are logical targets for drugs. For instance, the fibrates for serum triglyceride lowering are agonists of PPAR-alpha, while the insulin sensitivity increasing properties of the thiazolidinediones (glitazones) are based on their agonistic action toward PPAR-gamma. PPAR-gamma has been referred to as “the ultimate thrifty” gene, because of its ability to stimulate lipogenesis in the liver and adipose tissue (Auwerx, 1999). The unique 1300–1400 Å3 Y-shaped cavity that constitutes part of the PPAR lipid-binding domain may be at the basis of their promiscuous ligand-binding characteristics, but recent data suggest that fish oil fatty acids and notably their derivatives are among the most powerful naturally occurring PPAR ligands (Deckelbaum et al., 2006; Bragt and Popeijus, 2008; Itoh and Yamamoto, 2008; Gani and Sylte, 2008; Gani, 2008).

FIGURE 2.7. Role of PPARs in gene expression and repression.


Role of PPARs in gene expression and repression. Ligated PPARs heterodimerize with the ligated RXR to interact with a PPAR response element (PPRE). This interaction leads to the coordinated expression of many proteins involved in a variety of pathways. (more...) EFA and LCPUFA Deficiency and Marginality

Clinical signs of ω6 fatty acid shortage include growth retardation, reproductive failure, fatty liver, and a dry (scaly) skin that is characterized by augmented transdermal water loss. Deficiency of ω3 fatty acids may cause dysfunctioning of the central nervous system, including cognitive dysfunction and impaired vision. Biochemically, EFA deficiency (i.e., of both LA and ALA) gives rise to the accumulation of Mead acid (20:3ω9), because of the action of the chain elongation/desaturation system on the competing oleic acid (18:1ω9) (Figure 2.6). The order of substrate affinity of FADS2 is ALA > LA > oleic acid, which also explains the decrease of DHA with reciprocal increases of LCPω6, notably 22:5ω6 and to a lesser extent 22:4ω6 and AA, in isolated ALA deficiency. DHA may be conditionally essential (Muskiet et al., 2004), because of the difficulty by which it is synthesized and the relation of low DHA status with disease. “Conditionally essential” refers to a need of a dietary source during circumstances at which demand exceeds synthesis, such as during rapid growth, augmented nutrient loss, or declining synthesis, as for example, occurring in fetuses, young children, adolescents, pregnancy, lactation, and at advanced age. Age-dependent cutoff values for RBC 20:3ω9 (marker for EFA deficiency), RBC 22:5ω6/20:4ω6 (marker for ω3 deficiency), and RBC 22:5ω6/22:6ω3 (marker for ω3/DHA marginality and deficiency) have been proposed (Fokkema et al., 2002). Disbalances between AA, EPA, and DHA may change the ratio between EPA- and AA-derived eicosanoids with concomitant pathophysiological effects. For instance, there is a positive relation between the AA/EPA ratio in the platelets of different ethnic groups and the percentage of CAD deaths (Simopoulos, 2008). Competition between AA and EPA + DHA occurs to a large extent in compartments in which LCPUFA seem to have limited functionality apart from membrane flexibility or transport, such as RBC and plasma phospholipids. Consequently, measurements of LCPUFA in these compartments provide sensitive parameters for LCPUFA status assessment, of which the outcome is, however, as yet poorly defined in terms of pathophysiological consequences or disease risk. LCPUFA contents of RBC are considered a good reflection of brain LCPUFA (Makrides et al., 1994; van Goor et al., 2008a). The omega-3 index, that is, the sum of EPA and DHA in RBC, has been proposed as a risk factor for sudden cardiac death and may also serve as a fish oil treatment goal. An omega-3 index of >8 g/100 g RBC fatty acids (g%) is associated with 90% lower CAD risk, as compared with an index of <4% (von Schacky and Harris, 2007; von Schacky, 2008).

Biochemical and possibly clinical evidence of EFA deficiency is often present in protein-energy malnutrition (PEM). Typical symptoms in PEM, like skin changes, impaired resistance to infections, impaired growth rate, and disturbed mental functioning and development may be explained by coexisting EFA and LCPUFA deficiencies (Smit et al., 2002). Clinically apparent EFA deficiency in Western countries is rare. The sporadic cases are mostly based on heritable or acquired diseases that cause, or are accompanied by, poor gastrointestinal fat absorption. Inborn Errors and Polymorphisms

Demonstrated genetic defects in LCPUFA synthesis comprise FADS2 deficiency and peroxisomal beta-oxidation defects such as those occurring in the Zellweger syndrome and adrenoleukodystrophy (Jump, 2004). The FADS2 deficiency was caused by an insertion in its transcription regulatory region, leading to symptoms consistent with EFA deficiency with low AA and DHA. The clinical symptoms, such as corneal ulceration, feeding intolerance, growth failure, photophobia, and skin abnormalities, improved upon administration of AA and DHA (Williard et al., 2001; Nwankwo et al., 2003). Patients with generalized peroxisomal disorders such as present in Zellweger’s syndrome, have profound brain DHA deficiency. DHA supplementation improves their vision, liver function, muscle tone, and social contact, but the treatment should be initiated as soon as possible after birth (Martinez et al., 2000; Martinez, 2001).

At least 18 polymorphisms have been demonstrated in the gene cluster of FADS2 and FADS1. These polymorphisms exhibit a high degree of linkage disequilibrium and are accompanied by diminished FADS1 and FADS2 activities. Carriers of the minor alleles had higher LA, 20:2ω6, 20:3ω6, and 18:3ω3, together with lower 18:3ω6, AA, 22:4ω6, EPA, and 22:5ω3 in their serum phospholipids. The underlying allele(s) explained 28% of the interindividual serum phospholipid AA variability (Schaeffer et al., 2006). Polymorphisms of FADS2 were also found to influence the association between breastfeeding and higher IQ. Children carrying the investigated major allele who received breast milk had higher IQ compared with counterparts receiving infant formula. Those carrying the major allele benefited more from breastmilk than children carrying the minor allele, and this observation did not seem related to maternal genotype (Caspi et al., 2007). Recently we showed that the minor allele of a FADS1 polymorphism is associated with lower RBC AA in pregnant women and that this genotype is sensitive to further AA lowering following DHA supplementation (Dijck-Brouwer et al., 2008). The polymorphisms of FADS1 and FADS2 are clear examples of the many “disease susceptibility genes,” which do not cause disease by themselves, but only at unfavorable environmental conditions (here: low LCPUFA intakes). Their seemingly widespread occurrence might be taken as a testimony that the LCPUFA intakes from our ancient diet have been of sufficient magnitude to confer Darwinian fitness to their carriers.

2.5.2. LCPUFA in Pregnancy Maternal and Fetal LCPUFA Metabolism and Transplacental Transport

Women of reproductive age and pregnant women have higher fractional conversion of ALA to EPA and DHA than men (Burdge, 2006; Williams and Burdge, 2006). This higher efficiency might be important, but is unlikely to compensate fully for the fetal and newborn needs. Sensitivity of the desaturation/elongation pathway for hormones is supported by the observation in rats that serum estrogens and progesterone exhibit positive correlations with LCPω3 status, while testosterone is negatively related (Childs et al., 2008). It has been shown that the fetal baboon is able to synthesize DHA from labeled ALA and that labeled DHA is transferred across the baboon placenta. The placenta secretes apolipoprotein B-containing particles and contains both FADS1 and FADS2 activities. This suggests that placental LCPUFA synthesis may contribute to fetal LCPUFA status, but the extent to which this occurs is unknown (Innis, 2005). During pregnancy DHA becomes notably enriched in plasma PC, which is likely to augment DHA bioavailability to the placenta and fetus (Burdge et al., 2006). Transplacental fatty acid transport is selective for LCPUFA, as concluded from the higher LCPUFA contents in the fetal circulation, compared with the maternal circulation, while the transfer of LA and ALA is nonselective (van Beusekom et al., 1993; Duttaroy, 2004; Haggarty, 2004; Innis, 2005). The underlying mechanism of LCPUFA transplacental transfer, causing what has been named “biomagnification” (Crawford et al., 1976), is probably by a combination of many mechanisms, including selective hydrolysis of LCPUFA from maternal triglycerides, increasing maternal free fatty acids with advancing gestation in combination with higher fetal albumin, placental fatty acid-binding proteins (FABP) and fatty acid transfer proteins (FATP), a placenta-specific FABP with high DHA and AA affinity, and, importantly, the trapping of the transferred LCPUFA in the fetal circulation by albumin and alpha-fetoprotein or by esterification to lipids (Haggarty, 2004).

There is a nonsaturating linear relation between the phospholipid DHA/AA ratio in maternal and cord plasma for six populations with different fish intakes, including two with very high fish consumption (Otto et al., 1977; Jacobson et al., 2008). This relation coincided with rather uniform AA, but highly different DHA, in umbilical arteries and veins (Otto et al., 1997), suggesting that the current maternal DHA status does not cause saturation of transplacental DHA transport and that even higher infant DHA/AA ratios can be obtained at higher maternal DHA intakes. It has been suggested that AA does not become available for transport prior to the satisfaction of the high placental AA needs. The outcome of the various mechanisms is that fatty acids are transferred from mother to child with an order of preference of DHA > AA > ALA > LA (Haggarty, 2004). There is reasonable evidence to show that in Western countries the maternal body becomes somewhat depleted from LCPUFA, notably DHA, during pregnancy and subsequent breastfeeding. The following characteristics of LCPUFA physiology have been derived from the courses of the plasma phospholipids and RBC fatty acid compositions during pregnancy in Western countries: Maternal AA increases in early pregnancy and subsequently falls below prepregnancy levels, DHA increases in early pregnancy and remains above prepregnancy levels, the EFA/non-EFA ratio decreases while the DHA deficiency index (22:5ω6/22:4ω6) increases with gestational age, maternal and fetal LCPUFA (notably DHA) status are correlated, normalization of maternal DHA status after delivery is retarded by breastfeeding, and maternal plasma DHA is higher in primigravidae than multigravidae (Hornstra, 2000). Umbilical vessels at term (Muskiet et al., 2006) and RBC of newborns up to 0.2 years (Fokkema et al., 2002) contain relatively high amounts of Mead acid (20:3ω9, Figure 2.6; an index of EFA deficiency). Umbilical arteries contain higher 20:3ω9 than umbilical veins and each of these correlate inversely with corresponding AA and LA levels, and positively with 18:1ω9 levels. These data suggest that the intrauterine environment is characterized by low EFA status but may alternatively also be explained by the high fetal de novo fatty acid synthesis from glucose in the third trimester, causing increasingly successful competition of the novo synthesized 18:1ω9 for FADS2 and the occurrence of a state of “relative EFA/LCP deficiency,” rather than an absolute deficiency (Muskiet et al., 2006). Consequences of Low LCPUFA Status in Pregnancy

Mean EPA + DHA intakes by 19–30 years old Dutch females in 2003 has been estimated at 84 mg/day, while the current recommendation from 2006 is 450 mg/day (Kruizinga et al., 2007). An EFA deficiency initiated at conception in female mice caused biochemical signs of DHA depletion in maternal brain and severely impaired accretion of DHA and 22:4ω6 in the fetal brain. This implies that the growing fetal brain is more sensitive to low LCPUFA status development than maternal brain, at least in mice (van Goor et al., 2008a). More extreme models with long-term ALA deficiency in female rats showed that maternal brain DHA is vulnerable to depletion, which becomes aggravated by pregnancy and lactation (Levant et al., 2006a) and affects specific brain regions differently (Levant et al., 2007). Thus, because of the high fetal demands, it seems possible that the marginal LCPUFA status in Western countries causes maternal brain to lose LCP, notably DHA, during pregnancy. Declining maternal DHA status was suggested to be involved in the compromised selective attention (a key component of cognition) during pregnancy (de Groot et al., 2003) and may also be related to postpartum depression (Hibbeln, 2002). However, both the former and the latter hypothesis remained unproven in RCTs with ALA (de Groot et al., 2004) and LCPω3 (Freeman et al., 2006a, 2008; Sinclair et al., 2007; Rees et al., 2008), respectively. A recent small trial did, however, show beneficial effects of LCPω3 supplementation on depression during pregnancy (Su et al., 2008).

Low LCPω3 status in pregnant animals may cause inadequacies in retinal, brain monoaminergic and behavioral function in the offspring, which could not all be restored by an ω3 adequate diet (Innis and Friesen, 2008). Intrauterine LCPUFA status or its relation with other nutrients has as yet not been implicated in “programming,” but would be one of many plausible candidates, given the interaction of LCPUFA with various nuclear receptors (see Section For example, PPARs are involved in both growth and development. They are also likely to constitute a link between dietary fatty acids and one-carbon metabolism and thereby epigenetics, since folic acid supplementation of dietary protein-restricted pregnant rats corrected the overexpression of the PPAR-alpha gene in the fetal liver (Lillycrop et al., 2005). Folic acid-stimulated methylation of CpG dinucleotides in the PPAR-alpha gene promoter was found to be the underlying mechanism. These methylation patterns persisted into adulthood (Lillycrop et al., 2008) and were passed to the next generation (Burdge et al., 2007). Modifiable PPAR-alpha expression by maternal dietary protein and folic acid might be expected to confer different sensitivities of their offspring to PPAR-alpha natural ligands (such as LCPUFA and its metabolites), but its causal relation to “programming” has not been delineated as yet.

AA and DHA status of premature and low birth weight infants correlate positively with anthropometrics and length of gestation. AA correlates most strongly with anthropometrics (Koletzko and Braun, 1991; Leaf et al., 1992) and DHA with length of gestation (Olsen et al., 2006, 2007). Positive, negative and insignificant correlations between newborn AA and DHA status and birth weight have been noted in term infants (Elias and Innis, 2001; Rump et al., 2001; Lucas et al., 2004). The discrepancy with prematures might be caused by the rapid accretion of de novo synthesized fat in fetal adipose tissue near term. This interindividually variable compartment in size may confound the relation, since LCPUFA status is rather related to lean body mass than birth weight. Maternal DHA is positively related to birth weight and head circumference, while AA is negatively related (Dirix et al., 2008; van Eijsden et al., 2008). A meta-analysis of supplementation studies with LCPω3 during pregnancy indicated a mean increase of 1.57 days of gestation and a 0.26 cm increase of head circumference, but no influence on percentage preterm deliveries, low-birth-weight rate, or rates of preeclampsia and eclampsia (Szajewska et al., 2006). LCPω3 supplementation of women with high-risk pregnancies reduced the risk of early preterm delivery (i.e., <34 weeks), but there were no other effects on pregnancy outcomes such as recurrence of intrauterine growth retardation, and the rates of pregnancy-induced hypertension, preeclampsia, and caesarean section (Horvath et al., 2007). Trans fatty acids are negatively related to AA and DHA in umbilical vessels at birth and positively to Mead acid (Decsi et al., 2002). This relation probably indicates inhibition of LCPUFA synthesis by trans fatty acids and might be causal to their negative association with growth (Innis, 2006) and neurodevelopment (Bouwstra et al., 2006b), but other explanations are also possible (Innis, 2006).

A large observational study showed that 6 months to 8 years old children from mothers with seafood consumption below 340 g/week had lower verbal IQ, increased risk of suboptimal outcomes for prosocial behavior, fine motor skills, communication, and social development scores, compared with counterparts from mothers eating more than 340 g/week. The percentage of children with low verbal IQ was inversely related with the mother’s LCPω3 intake from seafood (Hibbeln et al., 2007). Higher cord plasma DHA was associated with a more optimal visual development at 6 months and cognitive and motor developments at 11 months (Jacobson et al., 2008), and with lower internalizing problem behavior at 7 years (Krabbendam et al., 2007). Others showed that maternal plasma phospholipid DHA is related to a more mature sleep pattern of their neonates (Cheruku et al., 2002) and that infants of mothers with high RBC DHA performed better on psychophysiological measures (4, 6, and 8 months) and on free play attention and distractibility paradigms (12 and 18 months) (Colombo et al., 2004). In addition, maternal DHA intake during pregnancy was associated with better stereo acuity of their children at 3.5 years (Williams et al., 2001). Not only DHA, but also AA is associated with neurodevelopment. A positive association was found between umbilical vessel AA and the neurological optimality score at 2 weeks (Dijck-Brouwer et al., 2005b), general movements at 3 months (Bouwstra et al., 2006a), and the neurological optimality score at 18 months (Bouwstra et al., 2006b). Maternal AA intake during pregnancy was related to shorter brainstem auditory evoked potentials of their infants at 1 month (Parra-Cabrera et al., 2008). Another study revealed no relation between umbilical blood DHA or AA status with child cognition at 4 years (Ghys et al., 2002) and 7 years (Bakker et al., 2003).

Several trials have been conducted in which pregnant women were supplemented with LCPω3. These showed no lasting effects on child visual and cognitive developments during the first year, but a number of these aiming at evaluation at later age have been positive (Innis, 2007a). Some studies showing no effect reported associations similar to those observed in observational studies (Malcolm et al., 2003). The discrepancy may relate to a complex interplay between a ceiling effect in the dose–outcome relationship, benefits to those with suboptimal baseline status only, and interindividual differences in developmental potential (Innis and Friesen, 2008). Studies with supplemental DHA dosages ranging from 200 to 2200 mg/day have mostly shown benefits with high dosages (Decsi and Koletzko, 2005). Interventions with supplemental dosages above 500 mg LCPω3 daily usually give rise to noticeable augmentation of fetal LCPω3 status (Velzing-Aarts et al., 2001). Higher IQ at 4 years was demonstrated after 1183 mg DHA + 803 mg EPA (total 2494 mg LCPω3) per day from the 18th week till the 4th month postpartum (Helland et al., 2003). No effect on mental and psychomotor developments and behavior were seen at 10 months in infants of mothers receiving 4 g fish oil (1.2 g DHA + 1.8 g EPA) daily during the last trimester of pregnancy (Tofail et al., 2006). Infants of mothers who consumed 214 mg DHA/day via a functional food from 24 weeks to delivery had higher visual acuity scores at 4 months, but not at 6 months (Judge et al., 2007a), and better problem solving abilities, but not recognition memory at 9 months (Judge et al., 2007b). Positive effects on eye and hand coordination was noticed in 2.5 years old children whose mothers received 2.2 g DHA + 1.1 g EPA daily from the 20th week until delivery (Dunstan et al., 2008).

Both maternal and fetal LCPUFA status are compromised by gestational diabetes mellitus (GDM), types 1 and 2 diabetes mellitus, and preeclampsia. This might be of growing importance because affluent countries experience increasing prevalence of overweight and obesity in pregnancy, while high maternal BMI is a well-established risk factor for diabetes mellitus, preeclampsia, and fetal defects. Higher 16:0 and lower AA and DHA in RBC (Min et al., 2006) with similar abnormalities in plasma (Thomas et al., 2005) were observed in women with GDM and their offspring (Min et al., 2006). Overweight and obese women with GDM had lower RBC AA and DHA than lean counterparts (Min et al., 2004). Fetal RBC AA and DHA were inversely related to HbA1c in healthy and GDM-complicated pregnancies (Wijendran et al., 2000), suggesting that fetal LCPUFA status is unfavorably affected by disturbed maternal glucose homeostasis. The placental phospholipids contained higher AA and DHA, whereas AA in placental triglycerides was lower (Thomas et al., 2005). Umbilical vessel walls of GDM and also type 1 diabetic pregnancies have lower EFA and LCPUFA status (Dijck-Brouwer et al., 2005a). Similarly, both AA and DHA status of pregnant women with types 1 and 2 diabetes and their newborns is lower than control (Ghebremeskel et al., 2004; Min et al., 2005). A number of studies have shown either higher AA, lower LCPω3, or lower PUFAω3 + ω6 in women with preeclampsia (Jensen, 2006). One case-control study showed higher potentially de novo synthesized fatty acids and lower LCPω3 and LCPω6 in umbilical vessels of preeclamptic births (Velzing-Aarts et al., 1999), which recently became confirmed in a population with high LCPω3 intakes from fish (Huiskes et al., 2009). The underlying mechanism of the lower fetal LCPUFA status in diabetes mellitus in pregnancy might be increased maternal free fatty acids and augmented fetal de novo fatty acid synthesis due to high transplacental glucose transport, causing dilution of LCPUFA (Dijck-Brouwer et al., 2005a; Muskiet et al., 2006). Compromised transplacental transport and higher de novo fatty acid synthesis in the maternal liver due to insulin resistance might be the cause of the lower LCPUFA status in the offspring of mothers with preeclampsia (Huiskes et al., 2009).

Taken together, both maternal and fetal DHA status might be at risk in current Western societies because of low maternal intake of fish and the increasing prevalence of maternal insulin resistance and compromised glucose homeostasis. The fetal preference of LCP, notably DHA, as compared with their parent EFA precursors is likely to point at the importance of fetal LCPUFA status. Positive effects of LCPω3 supplements on newborn neurodevelopment become especially noticeable at later age and following administration of high supplemental dosages from early pregnancy that are preferably continued during lactation.

2.5.3. LCPUFA in Neonatal Nutrition Importance of LCPUFA in Neonatal Nutrition

Brain volume is about 400 mL at birth and increases to about 1100 mL at the age of 2 years. AA and DHA are among the brain’s principal building blocks and it is clear that preformed DHA is more effective than ALA to cover the high prenatal (Greiner et al., 1997) and postnatal (Su et al., 1999; DeMar, Jr. et al., 2008) needs. Both preterm and term infants are able to convert LA to AA, and ALA to DHA (Innis, 2003), but the activity seems insufficient to keep postnatal LCPUFA status constant: numerous studies have shown a decline of AA and DHA in plasma and RBC of children receiving infant formulae without preformed LCPUFA, as compared to breastfed counterparts. A few autopsy studies on the corresponding brain LCPUFA levels have been conducted (Farquharson et al., 1992; Makrides et al., 1994; Martinez and Mougan, 1998; Jamieson et al., 1999). These revealed that infants receiving formula without DHA and AA had lower DHA in brain, but their AA was normal or somewhat higher. The brain DHA levels increased with age in breastfed infants, which was largely an effect of length of feeding, while the accretion of AA was dependent on age but not diet (Makrides et al., 1994). The lower DHA in frontal cortex PE, with concomitantly higher AA, 22:4ω6, and 22:5ω6, suggested low DHA status with compensatory chain elongation/desaturation of ω6 fatty acids (Innis, 2003). In other words, the occasionally higher AA and consistently lower DHA in the brain of formula-fed infants seem rather caused by DHA shortage with corresponding dominance of LCPω6 synthesis, notably of 22:5ω6, than by competition of DHA and AA for incorporation. The consequences in humans are as yet unclear, but partial replacement of DHA in the brain of rat pups with 22:5ω6, by either causing ω3 deficiency or postnatal feeding with 22:5ω6, led to loss of spatial task performance at adult age (Lim et al., 2005). Many functions of DHA in the brain are recognized to date, varying from membrane biogenesis, gene expression, neurite outgrowth, protection from oxidative stress and apoptosis, to modulation of neurotransmission (Innis, 2007a). Finally, low neonatal DHA status may be involved in “programming.” An ALA-deficient diet administered to rats in the perinatal period increased blood pressure in later life, even if they were subsequently repleted with ω 3 fatty acids (Weisinger et al., 2001). Consequences of Low Perinatal LCPUFA Status

Many, but not all, RCTs using formulae with and without LCPUFA and measuring outcome parameters like retinal function, visual acuity, behavior, and cognitive and motor developments, have shown positive effects of LCPUFA, notably DHA, in both preterm and term infants (Makrides et al., 2005; McCann and Ames, 2005; Hadders-Algra et al., 2007; Simmer et al., 2008a,b). Prematures are likely to benefit most, but many of the effects seem transient. The observed effects are especially on account of DHA, but addition of AA might be important to preserve ω3/ω6 balance. This might especially be appropriate at high EPA + DHA dosages for their ability to shut off AA synthesis from LA. What the ω3/ω6 or AA/EPA + DHA balances should look like is, however, uncertain, but the principal concern in Western societies is not AA but correction of our very low DHA status. It is in this respect of importance to note that differences in infant visual acuity have been found in the “normal” human milk DHA range, with high DHA corresponding to better visual acuity (Innis et al., 2001). Moreover, a recent study showed a relation between cord plasma DHA and better visual acuity and cognitive and motor developments in the offspring of Canadian Inuits, who have high intakes of marine foods (Jacobson et al., 2008).

A Cochrane meta-analysis based on 14 RCTs (11 of high quality) with relatively mature and healthy preterm infants showed (1) that most studies did not find differences in visual acuity over the first year, (2) that there was no effect on neurodevelopment at 12 or 18 months, and (3) that there were no effects on growth (weight, length, or head circumference) at 12 and 18 months. It was concluded that there are no clear long-term benefits for infants receiving formula supplemented with LCPUFA and that there is no evidence that formulas with LCPω3 and LCPω6 impair the growth of pre-term infants (Simmer et al., 2008b). Based on 14 RCTs (11 of high quality) a Cochrane meta-analysis with term infants showed (1) that data for visual acuity up to 3 years are inconsistent, (2) that there are no benefits on mental or psychomotor developments through the first 2 years, and (3) that there are neither beneficial nor harmful effects on growth through the first 3 years of life. The final conclusion was that there are no beneficial effects of LCPUFA supplementation of formula milk on visual, physical, and neurodevelopmental outcomes for infants born at term, and that LCPUFA supplementation cannot be recommended on the basis of current evidence (Simmer et al., 2008a). These conclusions are consistent with “no effect on growth” in an independent meta-analysis (Makrides et al., 2005) and with “no robust benefits of LCPUFA on mental and psychomotor developments in prematures between 12 and 18 postnatal months” (Smithers et al., 2008). LCPUFA also do not alter the risk of diseases of prematurity, such as necrotizing enterocolitis and neonatal sepsis (Smithers et al., 2008).

In contrast to the inconsistency of human studies, animal experiments have shown consistent abnormalities in various cognitive and behavioral tests, while also the beneficial effects of DHA (e.g., in CAD) in other human life stages cannot be ignored. More pronounced brain DHA deficiency (typically 70% depletion) in animal studies than those in humans (20% difference between brain DHA of breastfed and formula-fed infants), insufficient sensitivity of currently available tests in humans, and brain plasticity are among the possible explanations for the discrepancy (McCann and Ames, 2005). Also of importance might be that in the majority of studies neurodevelopmental outcome was assessed at 6–24 months, which is an age of “latency” in the expression of neurological dysfunction (Hadders-Algra et al., 2007). Therefore, on the basis of combined human and animal studies and because of the positive relations between neonatal brain DHA and cognitive and behavioral performance, the difficulty to detect differences by RCTs using the currently available tools, and the inability to exclude that LCPUFA have long-lasting beneficial effects on neurodevelopmental outcomes at school age and beyond, it is concluded that addition of LCPUFA and notably DHA to infant formula should rather be recommended on the basis of common sense than on the currently available strength of scientific evidence (McCann and Ames, 2005). Recommendations

Many recommendations for infant formulae have been issued by various nutritional boards and advisory committees. An example is AA ≥ 0.40 and DHA ≥ 0.35 g% for prematures and AA ≥ 0.35 and DHA ≥ 0.20 g% for term infants (Koletzko et al., 2001). These recommendations are based on the study of milk of mothers living in Western countries. However, these have low intakes of ALA, high dietary LA/ALA ratio, and limited consumption of fish, which relates to CAD, postpartum depression, and suboptimal neurodevelopment as outlined above. Criticizing their diet is inherent to criticizing their milk contents of AA and DHA (and other fatty acids), since both milk AA (Smit et al., 2000; van Goor et al., 2009) and DHA are notably dependent on long-term dietary habits, with the majority of the LCPUFA deriving from maternal stores (Fidler et al., 2000; del Prado et al., 2001). The milk fatty acid composition is strongly dependent on the dietary fatty acid composition and the carbohydrate energy percentage (Francois et al., 1998; Innis, 2007c; Kuipers et al., 2007). Worldwide the highest biological variation is in milk DHA and EPA and the lowest in 16:0. Among the EFA and LCP, AA and 20:3ω6 exhibited the lowest variation (Smit et al., 2002). The low worldwide AA biological variation might however be caused by the aforementioned relatively constant LA and AA intakes by Western populations. It was recently shown that maternal AA supplementation does increase milk AA (van Goor et al., 2009) and there is evidence from Vancouver that both milk DHA and AA have declined about 50% from 1988 to 1998 (Innis, 2003), while in the United States milk LA content has increased 2.5-fold from 1940 to 1990, with little change in ALA (Ailhaud et al., 2006).

Comparison of current recommendations for infant formulae with the actual fatty acid composition of human milk in various developing countries gives rise to many discrepancies and these are notably on account of the medium-chain fatty acids (12:0 and 14:0), LA and ALA, and also AA and DHA (Smit et al., 2003). For instance, the milk of the women living in Doromoni (Lake Kitangiri, Tanzania) contains relatively high percentages AA, DHA, and EPA, together with a relatively low AA/DHA ratio. Their diet is composed of sunflower oil-fried local fish, maize, and local vegetables (Kuipers et al., 2005). Milk from the island of Chole (Indian Ocean, close to the Tanzania mainland) contains high levels of 12:0, 14:0, AA and DHA, but low levels of LA that compare favorably with those in the United States in 1940. The staple foods in Chole are coconut and preferably boiled marine fish, which are combined with a high intake of fruits. Even higher milk DHA levels have occasionally been encountered in fish eating Caribbean societies (Kuipers et al., 2007) and other populations with high intakes of marine foods. Our rapidly changing Western dietary habits, the derivation of H. sapiens from the East-African land–water ecosystem (Broadhurst et al., 1998, 2002; Crawford et al., 1999; Gibbons, 2002a) and the more traditional lifestyle of the investigated women in some developing countries add to the contention that their milk fatty acid composition reflects a diet that is much closer to the ancient diet on which the genes of H. sapiens have evolved. It raises the question of who should actually constitute the H. sapiens standard.

The recent guidelines for LCPUFA contents of infant formulas and baby foods, as endorsed by the World Association of Perinatal Medicine, the Early Nutrition Academy, and the Child Health Foundation recommend to add at least 0.2 g DHA/100 g fatty acids (0.2 g%) in formulae for term infants. DHA should not exceed 0.5 g% and the minimum amount of AA should be equivalent to DHA (Koletzko et al., 2008). The basis of this recommendation is that at least 0.2 g% DHA is necessary to achieve benefits on functional endpoints, but that systematic evaluation of levels above 0.5 g% DHA was not published. The recommendations acknowledge that “breast is best,” that pregnant and lactating women should aim at dietary intakes of at least 200 mg DHA/day and that higher intakes up to 1 g DHA and 2.7 g LCPω3 have been studied without significant adverse effects. This new advice seems inconsistent because women who adhere to current recommendations for the general public to consume 450 mg LCPω3/day (about 170 mg DHA) or to the recommendations of the International Society for the Study of Fatty Acids and Lipids (ISSFAL) to consume 300 mg DHA/day during pregnancy and lactation (ISSFAL, 2008) will have mature milk DHA contents ranging from 0.43 to 0.79 g% DHA, but likely above 0.5 g% (van Goor et al., 2008b).

Taken together it seems that recommendations based on human milk observational, mostly Western, studies are likely to create a vicious circle: Low LCPUFA intakes by Western mothers cause low LCPUFA contents in breastmilk and correspondingly low recommendations for infant formulae, while both the consumption of LCPUFA-poor breastmilk and formulae will cause maintenance of low infant LCPUFA status (Brenna et al., 2007; Muskiet et al., 2007). Given the difficulty to proof beneficial effects of LCPUFA in infants, it might at present be a preferable strategy to aim at breastmilk DHA and AA contents of mothers consuming diets with RCT-proven benefits for CAD prevention in adults. The ultimate goal might, however, be to return to the human milk LCPUFA contents to which our genes have become adapted during evolution. The superiority of such diets might be difficult to prove in RCTs, but insistence on solid scientific evidence basically ignores the existence of evolution during which genes become adapted to environment and not vice versa.

2.5.4. LCPUFA in Psychiatric Disease LCPUFA and Brain

As outlined in the previous chapters, the brain has relatively high LCPUFA contents with functions in membrane-associated processes and eicosanoid production and also in gene expression. “Nutrigenomics” studies in rats revealed that LCPω3 modulate the expression and repression in brain of a sizeable number of genes that are involved in structure, energy metabolism, neurotransmission, signal transduction, and regulation (Kitajka et al., 2002, 2004). A study with newborn baboons showed that dietary DHA and AA dosages within the human milk intake range caused differential expression of many genes involved in lipid metabolism and transport, G-protein and signal transduction, development, visual perception, cytoskeleton, peptidases, stress response, transcription regulation, and others without defined function (Kothapalli et al., 2007). PPAR-gamma is abundant in mouse embryonic brain and both AA and DHA are ligands of RXR, which as a heterodimer with the retinoic acid receptor (RAR) regulates expression of many genes involved in development, such as those involved in neurogenesis, differentiation, and plasticity (Innis, 2007a). Dietary LCPUFA also infiuence neurotransmitter physiology and behavior. Experiments with young rats revealed that fish oil supplementation influences several neurochemical and behavioral features of monoaminergic function, causing an increase of cerebral membrane PS, higher dopamine, reduction of monoamineoxidase-B activity and greater binding to dopamine D2 receptors in the frontal cortex, and also lower ambulatory activity (Chalon et al., 1998). Profound chronic dietary ALA deficiency decreased the brain dopamine pool in the frontal cortex, which relates to hypofunction of dopaminergic transmission in the frontal cortex, and to hyperfunction in the nucleus accumbens (Chalon et al., 2001). Variation in rat brain DHA content by dietary means was found to cause sex-specific alterations in locomotor activity, with males being most affected notably at postadolescent age. The observed DHA content–effect curve was bell-shaped, with both low and high brain DHA giving rise to lower locomotor activities compared with control and medium high DHA levels (Levant et al., 2006b). Not only the dopaminergic, but also the serotonergic and cholinergic systems are influenced and, importantly, not all of the abnormalities proved correctable by reversal diets. Their persistence throughout life suggests that disbalances of ω3 and ω6 fatty acids, notably low DHA, in early life might have long-term consequences in neurotransmission systems and thereby brain functioning, and that these may be related to neurological and psychiatric disorders (Chalon, 2006).

A recent review (McNamara and Carlson, 2006) concluded that studies in rodents have shown that DHA is important in the developing brain because of its neurotrophic properties in the promotion of neuronal arborization and synaptogenesis. The frontal cortex and hippocampus are the most sensitive to dietary DHA deficits and such deficits notably affect the developing brain as opposed to the fully matured brain. Low brain DHA is accompanied by a reciprocal increase of 22:5ω6 and a decrease of PS, and is associated with reduced extracellular levels of various neurotransmitters including serotonin, dopamine, and acetylcholine upon stimulation, along with increased serotonin receptor-binding density, and reduced dopamine receptor-binding density. Most of these abnormalities proved correctable if feeding with dietary ω3 fatty acids was initiated within the first two postnatal weeks, but not beyond, suggesting that there is a critical window of opportunity for normalization. Perinatal ω3 deficiency in rodents is related to abnormal spatial learning, working memory and olfactory discrimination learning, anxiety, aggression, depression, and deviant locomotor activity upon treatment with various drugs, including amphetamine and scopolamine. Experiments with nonhuman primates showed that prematurely born monkeys had lower brain DHA than term counterparts. Initiation of an ALA-low diet prior to conception caused low brain DHA in the offspring and reduced visual acuity. The DHA deficits proved slowly correctable by a postnatal high-ALA feeding regimen, with retinal DHA showing the slowest recovery. The ω3 deficiency in non-human primates is associated with reduced visual acuity, abnormal electroretinograms, polydipsia, and longer look duration to both familiar and novel stimuli. LCPUFA and Behavior

Current research in psychiatric disease seems to fall short of the input of nutrition and may be somewhat overdosed with genetics and the traditional search for abnormal neurotransmitter metabolism per se. Low perinatal frontal cortex DHA accretion is associated with suboptimal development of the dopaminergic system and therefore a risk factor for attention-deficit/hyperactivity disorders (ADHD) and schizophrenia. These anomalies may still be correctable within a certain perinatal time window but not beyond, which might explain the limited efficacy of supplementation studies at later age (McNamara and Carlson, 2006). It is possible that also the relation of LCPUFA with one-carbon metabolism is involved, since at least schizophrenia is strongly related with low intrauterine folate status (Muskiet and Kemperman, 2006). Low intake of the fish oil fatty acids EPA and DHA is implicated in the high incidence of depression in Western countries. This incidence has increased markedly in recent decades (Klerman and Weissman, 1989) and there is a strong inverse correlation between national dietary fish intakes and rates of major and postpartum depression (Hibbeln, 1998, 2002). Depressive symptoms are more likely to be encountered in infrequent fish consumers. Patients with depressive symptoms have low EPA and DHA status and their AA/EPA ratio is high (Freeman et al., 2006b), while plasma EPA in the elderly is inversely related to the severity of depressive symptoms (Feart et al., 2008). The close relationships between fish consumption and the incidence of CAD (see Section 2.4.2) and depression has fuelled the suggestion that depression should be included into the cluster of diseases that are associated with the metabolic syndrome (Peet, 2003).

Multiple hit scenarios have been proposed to explain the late onset of psychiatric diseases, such as schizophrenia. Initial hits may occur in the uterus, or even during gametogenesis, with subsequent insults occurring in adolescence or adulthood, causing accumulating epigenetic abnormalities (“epimutations,” Petronis, 2004). There is indeed good evidence to show that birth weight and pregnancy complications are risk factors for the development of at least some psychiatric diseases, including schizophrenia (Godfrey and Barker, 2000; Wahlbeck et al., 2001). Very-low-birth- weight babies are at risk for developing psychiatric symptoms and reduced social and academic skills at adolescent age, while term small-for-gestational age babies have higher risk of emotional, behavioral, and attention deficit symptoms (Indredavik et al., 2005). A study of perinatal risk factors for autism concluded that we might be dealing with risk factors for obstetric complications and that these may precipitate to autism by exposure to certain environmental stimuli (Glasson et al., 2004). Low birth weight was also noticed as a perinatal risk factor in another autism case-control study (Larsson et al., 2005). A meta-analysis of prospective population-based studies revealed that schizophrenia is associated with complications of pregnancy, abnormal fetal growth and development, and complications of delivery (Cannon et al., 2002). Dietary habits at young adult age may constitute the basis for a second hit. Data from the United Kingdom show that the peak age of schizophrenia onset (i.e., 19–24 years) coincides with the highest intake of burgers (i.e., saturated fat) and full-sugar carbonated drinks and the lowest intake of oily fish (Peet, 2004b). A meta-analysis of dietary patterns in various countries linked the intake of refined sugar and dairy products to a worse 2-year outcome of schizophrenia, while a high national prevalence of depression became predicted from low intake of fish and seafood (Peet, 2004a).

The outcome of RCTs have until now been rather disappointing, with some exceptions, notably in depression. A 2006 Cochrane meta-analysis concluded that the use of LCPω3 for schizophrenia treatment remains experimental and that there is a need for large well-designed, conducted, and reported studies (Joy et al., 2003). This outcome is in line with two other meta-analyses concluding that “LCPω3 failed to improve schizophrenia symptoms” (Freeman et al., 2006b) and that the “available data are not supportive of the efficacy of LCPω3 in schizophrenia” (Ross et al., 2007). Two meta-analyses of RCTs showed beneficial effects of LCPω3 in patients with affective disorders (i.e., combined unipolar and bipolar depression) although the results were highly heterogeneous (Freeman et al., 2006b; Lin and Su, 2007). It was felt that more large-scale well-controlled trials were needed to identify favorable target subjects with mood disorders, therapeutic dosages, and LCPω3 compositions (Lin and Su, 2007). These conclusions are largely in agreement with two other recent reviews in which a dosage of 1–2 g LCPω3/day was considered to be effective (Ross et al., 2007) and in which it was noted that 7 out of 10 studies in adults with depression or bipolar disorders showed positive effects of either fish oil or ethyl EPA, while three were negative (Sinclair et al., 2007). A recent small RCT with LCPω3 supplementation in children with autistic disorders showed a trend for beneficial effects in hyperactivity and stereotypy (Berger et al., 2008). On the other hand, no beneficial effects of LCPω3 were noted in ADHD (Freeman et al., 2006b; Ross et al., 2007) and LCPω3 can therefore not be recommended as a primary treatment (Richardson, 2006). A combination of ω3 and ω6 supplements have shown benefits in three studies with ADHD patients (Freeman et al., 2006b) and a recent study revealed beneficial effects of an elimination diet (Pelsser et al., 2009). LCPω3 may also reduce aggression, impulsivity, and hostility in subjects with borderline personality disorder, the normal population, children with ADHD and reduce felony-level violence in prisoners, although the latter study also provided a multivitamin and mineral supplement (Freeman et al., 2006b).

Taken together, the current data suggest that low LCPω3 status is likely to be involved in the etiology of at least some psychiatric diseases, but also their presentation in terms of disease severity at later age. A fetal origin may prove difficult to correct, but this does not hold for the often poor nutritional status, including biochemical EFA deficiency and folate-sensitive hyperhomocysteinemia, that may be encountered in at least some psychiatric patients (Kemperman et al., 2006). The latter is of importance since contrary to popular belief the primary cause of death in schizophrenia is not suicide, but CAD, while they have high risk of diabetes, partially because of the use of the new generation antipsychotics. Basically, there seem to be little difference in the dietary risk factors for poor mental health, CAD, and some cancers, which adds to the notion that we are dealing with common insults that originate from our changed environment, produce adverse effects in different organs and systems at different life stages, affect the genetically most vulnerable first, but will with increasing dose and exposure time ultimately affect all of us. Schizophrenia Phospholipid Hypothesis

There are (anecdotic) reports that (1) feverish illness in patients with schizophrenia ameliorates their psychiatric symptoms, (2) patients with schizophrenia rarely suffer from rheumatoid arthritis (suggesting a generalized reduced inflammatory response), (3) schizophrenic patients are less capable of producing the typical (prostaglandin-induced) cutaneous flush that follows nicotinic acid ingestion or topical application, and (4) schizophrenia in developing countries, with usually higher LCPUFA intakes, runs a less severe course (Christensen and Christensen, 1988; Hopper and Wanderling, 2000; Horrobin, 2001; Peet, 2003). Horrobin (2001) linked these observations to the so-called phospholipid hypothesis stating that schizophrenia is a systemic disease with a central theme of insufficient AA release for the production of its eicosanoid metabolites to support adequate signal transduction (Horrobin, 1998). It was suggested that the disease might find its origin in a genetically determined generalized “abnormality” of phospholipid metabolism that is sensitive to prevention or may even become corrected in part by nutritional factors, including LCP. The postulated polymorphism(s) of patients with schizophrenia might in the past not have precipitated to disease since the LCP-rich diet of our ancestors enabled them to take full evolutionary advantage of the intelligence and creativity that is associated with schizophrenia (Horrobin, 2001). LCPUFA and Low-Grade Neuroinflammation in Psychiatry: A Common Denominator?

Consistent with the increased LCPUFA losses postulated by the phospholipid hypothesis, both patients with schizophrenia (Peet, 2003; Ross, 2003) and autism (Bell et al., 2004) have increased activity of PLA2, which releases AA from membrane phospholipids (a process vital to brain cell signaling), while their LCPUFA in RBC appear more sensitive to oxidative stress in vitro (Fox et al., 2003; Bell et al., 2004). Brain magnetic resonance spectroscopy studies in patients with schizophrenia showed signs of increased phospholipid turnover, electroretinograms of patients with schizophrenia are abnormal (suggesting low retinal DHA content), while incorporation of AA into phospholipids seems to occur with difficulty (Horrobin, 2001). Taken together, these data suggest local AA depletion and insufficient synthesis of certain AA-derived eicosanoids, which becomes, for example, noticeable by amelioration of psychiatric symptoms initiated by fever-associated eicosanoid release, pain resistance by eicosanoid shortage at basal conditions, and poor ability to exhibit an eicosanoid-induced flush upon nicotinic acid treatment. It was hypothesized that perinatal supplementation of LCP, especially EPA and DHA, may prevent schizophrenia in the adult. Schizophrenia has also been suggested to derive from low-grade systemic inflammatory disease with origins in the perinatal period, probably triggered by maternal infection in a genetically susceptible individual, leading to excess production of proinflammatory cytokines in both mother and fetus. The inflammation compromises LCPUFA status with devastating neurodevelopmental effects that should theoretically be favorably responsive to augmented LCPUFA status (Das, 2004).

It is nowadays widely recognized that insulin resistance and its sequelae associated with the metabolic syndrome (such as diabetes type 2, CAD, and certain cancer types) and neurodegenerative disorders (like Alzheimer’s disease and Parkinson’s disease) and depression may have a common origin in a state of low-grade inflammation that finds at least part of its origin in the currently high dietary intakes of SAFA, trans fatty acids and ω6 fatty acids, and the low intakes of ω3 fatty acids, notably those abundant in fish (Innis, 2007b). The resulting high ratio between AA and EPA + DHA might have driven us into a proinflammatory condition that may precipitate to a hyperinflammatory response upon a trigger (the “systemic inflammatory response syndrome;” SIRS) with collateral damage, scarring and fibrosis, and the subsequent development of immune paralysis (“compensatory anti-inflammatory response syndrome;” CARS) characterized by weakened host defense and susceptibility to (secondary) infections (Mayer and Seeger, 2008). The putative normal immune response requires lipid mediators from both AA and EPA + DHA, in which those from AA are implicated in the initiation of the inflammatory reaction and also in the lipid mediator “class switch” to those of EPA and DHA, which are responsible for the termination and complete resolution of the immune reaction and return to homeostasis (see Sections 2.4.2 and (Serhan et al., 2008). The chronic inflammation resulting from the unbalanced AA/EPA + DHA ratio might be central in the pathogenesis of the diseases of the metabolic syndrome and neurodegenerative disease, explain the relation between inflammation, depression, and dementia (Leonard, 2007), and explain the favorable effects of LCPω3 supplements, although these are not consistently observed. LCPω3 supplements might especially be effective in prevention. This is, for example, suggested by the outcomes of epidemiological studies on CAD and prospective studies on Alzheimer’s disease (Bourre, 2005), and also from the favorable effects of LCPω3 in early disease stages. For instance, it was recently shown that LCPω3 supplements are effective in cognitive function in patients with mild cognitive impairment, but not in those with mild or moderate Alzheimer’s disease (Chiu et al., 2008).

Mechanistically it has been shown in rats that about 5% of both brain AA and DHA per day is lost by metabolism and subsequently replaced (Rapoport, 2003). Brain DHA supply is dependent on dietary sources and its limited synthesis from ALA notably in the liver (Rapoport et al., 2007), while the efficiency of brain DHA synthesis during ALA deficiency does not become upregulated (Igarashi et al., 2007). Consequently, deprivation of dietary ω3 fatty acids lowers DHA in rat brain, and also lowers the activity of the DHA regulatory PLA2 (i.e., calcium-independent iPLA2) and COX1 in rat frontal cortex, and increases the activity of the AA selective calcium-dependent cytosolic PLA2 (cPLA2), secretory PLA2 (sPLA2), and COX2. The outcome is an increased half-life of brain DHA by downregulated iPLA2, but augmented release of AA and production of its eicosanoid metabolites and other bio-active mediators involved in brain signaling and neuroinflammation. In other words, low brain DHA indirectly augments susceptibility to inflammation and other brain insults through an upregulated brain AA–COX2–prostaglandin cascade (Rao et al., 2007). An upregulated AA–COX2–prostaglandin cascade is present in acute neurological disorders, such as cerebral ischemia and head trauma, but also in chronic neurologic disorders, such as Alzheimer’s disease and Parkinson’s disease, while decreased DHA and its anti-inflammatory docosanoids have been demonstrated in postmortem brain samples from patients with Alzheimer’s disease (Orr and Bazinet, 2008). Mood stabilizers like lithium, valproate, and carbamazepine inhibit the AA cascade by reducing AA turnover, but not DHA turnover, in rat brain phospholipids (Rao et al., 2008). These findings are to a large extent supportive for the phospholipids hypothesis of Horrobin.


H. sapiens has evolved on a diet that was high in ALA from vegetable sources, rich in AA, EPA, and DHA from a land–water ecosystem (including (lean) fish) and contained low LA, SAFA, and no trans fatty acids from industrial sources. We have, however, gradually changed this diet from about 10,000 years ago and accelerated these changes from about 100–200 years ago. These, but also other, dietary changes are firmly implicated in the risk of typically Western diseases. Some of the relations, for example, the association of ALA and fish oil with CAD and LCPω3 with depression, have proven their causalities in intervention trials. Evolutionary medicine, and perhaps common sense, teaches us that we might have to return to the composition of the diet on which our genes have evolved. For this, we need rethinking of the very basics of “homeostasis” and avoidance of the vicious cycle that is initiated by taking observations from Western societies as a basis of dietary recommendations and lifestyle in general. Traditionally living societies may provide us with clues for absolute standards for human homeostasis, but unfortunately many of these have meanwhile become dependent on food programs with typically Western approaches (e.g., high carbohydrates), or adopted a (quasi) Western lifestyle in general. It may be questioned whether definite answers will come from the expensive RCT approaches of single nutrients, since these require large study numbers, long observation periods, elucidation of dose–response relationships, and investigation of numerous interactions with other nutrients (for example: one-carbon metabolism and LCPUFA). A combination of data from traditionally living societies, (patho)physiological insight, anthropometrics, archeology, genetics, nutrigenomics, and classical trials may lead to cleverly designed RCTs to answer the question on what diet our genes have evolved and what diet consequently promotes our health at best. The lessons from such studies might especially be relevant to early nutrition, because of its importance to development and the increasingly recognized relation between early development and the risk of disease at later life.



arachidonic acid


adequate intakes


alpha-linolenic acid


acceptable macronutrient distribution range


body mass index


coronary artery disease


carbohydrate regulatory element-binding protein


central nervous system

COX1 and COX2

cyclooxygenases 1 and 2


dihomo-gamma-linolenic acid


docosahexaenoic acid


developmental origins of health and disease


dietary reference intakes


essential fatty acids


energy %


eicosapentaenoic acid


fatty acid-binding protein


fatty acid desaturase 1 (delta-5 desaturase)


fatty acid desaturase 2 (delta-6 desaturase)


fatty acid-transfer protein


gestational diabetes mellitus


gamma-linolenic acid


glucocorticoid receptor


high-density lipoprotein




linoleic acid


long-chain polyunsaturated fatty acids


low-density lipoprotein




Max-like factor X


methylenetetrahydrofolate reductase


monounsaturated fatty acid


predicted adaptive response




pathobiological determinants of atherosclerosis in youth




protein-energy malnutrition




phospholipase A2


peroxisomal proliferators-activated receptor




polyunsaturated fatty acid


retinoic acid receptor




randomized controlled trial


recommended dietary allowance


retinoid X receptor


saturated fatty acid


sterol regulatory element-binding protein


unsaturated fatty acid


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Any energy-containing foods that displace breastfeeding and reduce the intake of breast milk.


Long-chain polyunsaturated fatty acids are straight-chain fatty acids with ≥20 carbon atoms and ≥3 double bonds in the methylene-interrupted cis configuration.


The metabolic syndrome, also referred to as the insulin resistance syndrome, is a combination of four frequently occurring symptoms, i.e., high blood pressure, disturbed glucose homeostasis, dyslipidemia, and overweight. The syndrome confers high risk of diabetes mellitus type 2, cardiovascular disease, and many other typically Western diseases. Microalbuminuria is a symptom that is also considered to be part of the metabolic syndrome by some.


Thrifty genotype hypothesis: limiting food recourses have in the past favored alleles that promote efficient bodily storage of energy reserves. In conditions of plentiful nutrition, this genotype predisposes to disease. Thrifty phenotype hypothesis: limiting food resources cause physical and metabolic adaptations of the fetus that, when mismatched predisposes to disease in later life.


The extent to which an organism is adapted to or able to produce offspring in a particular environment.

Homeostasis is the “integration of, and the balance between, physiological functions.” It refers to optimal interaction between environment and our genome: “our nature in balance with nurture.”


Epigenetics is the study of the changes in gene expression that occur without changes in DNA sequence. These changes are inherently unstable, but stable during mitosis (by which a liver cell remains a liver cell) and occasionally during meiosis (in which case phenotype is transmitted to the next generation). Epigenetics is at the basis of the phenotypic differences between a liver cell and neuron carrying the same genome. The environment transmits instructions to the genome through epigenetics to keep our phenotype perfectly adapted at both short and middle-long term.


Fatty acids are denoted as a:bωc, in which a is the (usually even) number of straight chain carbon atoms, b the number of double bonds in the methylene-interrupted cis configuration, and c the number of atoms from the methyl end to the first double bond.

Polymorphism refers to differences in DNA sequences that occur with ≥1% frequency in the population. A mutation has a frequency <1%.