18.1. INTRODUCTION

A fatty acid is a carboxylic acid often with a long unbranched aliphatic chain and is divided into two categories based on structural and chemical properties: (1) saturated and (2) unsaturated. Saturated fatty acids do not contain any double bonds or other functional groups along the chain. Unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond enabling the addition of other atoms to these carbons. Distinction between the two is simply that saturated fatty acids are usually solid at room temperature whereas unsaturated fatty acids are liquid. Unsaturated fatty acids can be further divided into monounsaturated (which contains only one double bond) or polyunsaturated fatty acids (PUFAs), which contain more than one double bond. PUFAs are further grouped based either on the location of the double bonds and/or according to the chain length. An omega (ω ) notation indicates the number of carbon atoms from the methyl end to the first double bond. Omega-3 (ω – 3 or n – 3) and Omega-6 (ω – 6 or n – 6) are two well-known fatty acids that are termed “essential fatty acids” (EFA). Such EFA are obtained from diet since they cannot be manufactured by cells (double bonds can be introduced into all positions of the fatty acid chain except the n – 3 and n – 6 positions). α-Linolenic acid (ALA) is an ω – 3 fatty acid that is converted to eicosapentaenoic acid (EPA) and subsequently from EPA to docosapentaenoic acid (DPA) and then to docosahexanoic acid (DHA). Linoleic acid (LA) is the parent fatty acid for ω – 6 class of fatty acids. LA is converted to γ-linoleic acid (GLA) which through subsequent conversions results in the formation of arachidonic acid (AA) and is a precursor for several classes of eicosanoids. In the nervous system, cell membranes contain relatively high concentration of PUFAs, such as docosahexaenoic acid (DHA) (Stillwell and Wassall, 2003).

In this review we provide a synthesis of evidence concerning the neural and hormonal control on food intake with a special emphasis on long-chain fatty acids. Fatty acids act on the central nervous system (CNS) as important physiological regulators of energy metabolism and overall energy homeostasis. In addition, we will examine evidence on key neural structures and systems influenced by fatty acids that are involved in feeding behavior. Lastly, we will review evidence on the role of EFA in preventing cognitive decline as well in neurological disorders.

18.2. NEURAL AND HORMONAL REGULATION OF FATTY ACIDS

Maintenance of energy homeostasis is critical to the well-being of an individual as excess energy balance can lead to increased adiposity. A complex physiological system regulates energy intake and expenditure composed of both afferent and efferent signals to and from the brain, respectively. These signals include glucose, lipids, peptides as well as steroids, all of which influence appetite. Links between peripheral signals and the brain to regulate food intake are complex and several hypotheses including the glucostatic (Mayer, 1953, 1955, 1996) and lipostatic (Kennedy, 1953; Mayer, 1955) hypotheses have been proposed to explain their interrelationship. Based on the observation that neurons primarily use glucose, the glucostatic theory posits that food intake is determined by the use of glucose by neurons and fluctuations in glucose availability or usage are linked to food intake. If glucose availability is low, neurons would be activated and hunger increased but when the rate of glucose utilization is high, the activity of the brain cells sensitive to glucose is diminished (see Levin et al., 2004). Thus energy intake would keep up with energy expenditure and thereby maintain energy balance. A major difference between peripheral tissues, such as muscle and the brain is that the neurons cannot store glucose, indicating that the metabolism of glucose may have a unique place in the regulation of appetite. Lipostatic theory is based on the observations that neurons monitor the levels of circulating lipids which is indicative of the nutritional status and that lipid storage in the organism is connected to the neuronal or hormonal control of appetite. Thus, according to this theory, circulating levels of hormones including leptin or insulin, as well as substrates such as fatty acids, modulate hypothalamic function in determining appetite. While both glucostatic and lipostatic theories have studies supporting their hypothesis, energy regulation is far more complex and likely both mechanisms influence each other in the CNS to regulate overall energy homeostasis.

Investigations into the neural control of energy balance began with studies that showed lesions of specific nuclei in the hypothalamus could either produce increased or decreased food intake in animals depending on the location of the lesion (Anand and Brobeck, 1951; Stellar, 1954). In addition to the hypothalamus, other centers in the brain that contribute to appetite control include the brain stem (Carlisle and Reynolds, 1961), limbic structures, and the cerebral cortex (Grossman and Grossman, 1963; see Berthoud, 2002 for review). A neural network that includes these structures, with coordinated signals amongst them, likely influences energy regulation in the organism. Traditionally, adipose tissue, liver, and skeletal muscle have been the focus of such research, but the role of CNS in sensing the energy needs of the organism and conveying such information to the peripheral centers is vastly appreciated. Most research, however, centers on the role of the hypothalamus. The hypothalamus in the brain contains nuclei that control energy homeostasis as well as the regulation of food intake generally by altering the expression of neurotransmitters or neuromodulators (Kalra et al., 1999). The arcuate nucleus (ARC), which is located around the base of the third ventricle, responds to circulating levels of leptin, ghrelin, and insulin. The ARC, surprisingly, is not protected by the blood–brain barrier (BBB) (Brightman and Boradwell, 1976) but not all circulating hormones cross the BBB freely to influence the ARC (Banks et al., 1996; Banks, 2004) indicating a likely regulatory mechanism at the BBB. Two major nuclei in the ARC that play important roles in feeding are (1) the ventromedial nucleus of the ARC that contains the orexigenic (feeding promoting) center and expresses neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY) (Broberger et al., 1998; Hahn et al., 1998) (2) ventrolateral nucleus of the ARC contains cells that are anorexigenic (feeding inhibitors) and expresses proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) and cocaine- and amphetamine-regulated transcript (CART; Elias et al., 1998; Kristensen et al., 1998). Melanocortin receptors, receptors for MSH, and adrenocorticotropic hormone (ACTH), are a subfamily of G protein-coupled receptors (Adan and Gispen, 1997) that consist of at least five subtypes. α-MSH secreted from POMC/CART neurons acts on melanocortin 3/4 receptors in the hypothalamus, whereas AgRP secreted from NPY/AgRP neurons acts on these receptors as an antagonist. Thus, melanocortin 3/4 receptors in the hypothalamic neurons play an integral role in the central control of appetite and energy expenditure.

Extensive reciprocal connections exist between the hypothalamus and the brainstem, particularly the nucleus of the solitary tract (NTS) (Ricardo and Koh, 1978). The NTS lies in close proximity to area postrema, which benefits from some lack of the BBB, and thus may be influenced by circulating levels of hormones or fatty acid metabolites. NTS has a high density of NPY-binding sites (Harfstrand et al., 1986) and NPY-expressing neurons (Sawchenko et al., 1985). In addition, melanocortin four receptors are also expressed in the brainstem (Mountjoy et al., 1994).

The corticolimbic structures play an important role in appetite regulation likely by modulating reward, cognitive, and emotional factors. Using functional magnetic resonance imaging (fMRI) to investigate activation of reward system in the brain, Stoeckel et al. (2008) reported that pictures of high-calorie foods produced significantly greater activation in the cortex, hippocampus, and striatum of obese subjects when compared to controls. Neurobiological responses in obese subjects to an implantable gastric stimulator (IGS), which induces stomach expansion via electrical stimulation of the vagus nerve, showed increased metabolism in the hippocampus as assessed by positron emission tomography and 2-deoxy-2[¹⁸F]fluoro-d-glucose (Wang et al., 2006), indicating the importance of the hippocampus in modulating eating behaviors linked to emotional eating. A recent study indicated that in rodents, gastric electric stimulation may increase the expression of cholecystokinin (CCK), a hormone, in the hippocampus (Xu et al., 2008) and thus may be involved in inhibiting food intake. In addition, CART, POMC, NPY, and AgRP mRNAs are all expressed in the adult human hippocampus (Bai et al., 2005) as well as in rat hippocampus (Bai et al., 2005 and references therein), but their role in regulating appetite is not clear.

Numerous hormones play a key role in appetite regulation generally through their action on neural centers. Adipocytes, the gastrointestinal tract, and the pancreas are some of the major sites of hormone production in the periphery. One of the first hormones from the periphery implicated in the regulation of metabolism is CCK (see Beglinger, 2002, for review). CCK acts on the peripheral vagal afferent receptors to inhibit food intake, through its eventual actions on the brainstem. As mentioned above, CCK may also exert its effects on the hippocampus.

Leptin, an endocrine hormone and a product of ob gene, is secreted predominantly by adipocytes and acts on the hypothalamus. Leptin reduces adipocity and is another example of the endocrine-brain signaling pathway that regulates food intake. In the CNS, leptin acts to suppress appetite and increase energy metabolism (Halaas et al., 1995; Pelleymounter et al., 1995). Leptin administered peripherally (Pelleymounter et al., 1995; Hwa et al., 1997) or centrally (Hwa et al., 1996) to ob/ob mice reduces appetite, decreases fat mass, and increases metabolic rate. In the CNS, leptin receptors in the hypothalamus (Tartaglia et al., 1995) are hypothesized to mediate satiety by decreasing NPY levels (Campfield et al., 1995; Stephens et al., 1995) and/or by increasing metabolism through activation of the efferent sympathetic system (Campfield et al., 1996a,b). In the periphery, the mechanism of action of leptin, as studied in cell cultures and isolated tissue, is postulated to be through its effects on increasing metabolism primarily by intracellular lipolysis and fatty acid metabolism (Koyama et al., 1997; Shimabukuro et al., 1997).

Insulin is an important hormone that regulates food intake. Insulin is produced by the pancreas. Levels of insulin vary with adiposity (Bagdade et al., 1967). Central administration of insulin decreases food intake in primates (Woods et al., 1979) as well as in rats (Ikeda et al., 1986; Menendez and Atrens, 1991) and hypothalamus is implicated in insulin’s action in reducing food intake (Strubbe and Mein, 1977; Menendez and Atrens, 1991).

Ghrelin is an orexigenic factor that is released from the stomach, duodenum, and ileum (Kojima et al., 1999; Date et al., 2000), and plasma ghrelin levels are inversely correlated with body mass index, a measure of obesity (Otto et al., 2001). Central or peripheral administration of ghrelin increases food intake and body weight in rats (Tschop et al., 2000; Wren et al., 2001b). Intravenous administration of ghrelin to healthy human subjects also stimulates food intake (Wren et al., 2001a). Ghrelin is hypothesized to exert its action on the ARC in the rat hypothalamus (Tamura et al., 2002). Other hormones secreted by endocrine glands also affect energy balance including thyroid hormones, corticosterone, and growth hormones (see Kalra et al., 1999; Coll et al., 2007 for reviews). The exact mechanism by which such hormones act, whether alone or in concert, to regulate food intake is not clear.

Another class of molecules that also influence appetite is members of the fatty acid biosynthetic pathway including malonyl-CoA, an intermediate of fatty acid biosynthesis. Fatty acid oxidation plays a key role in the control of food intake. Evidence indicates an important role of fatty acids in the CNS where it plays a key role in physiological regulation of glucose metabolism and general energy homeostasis (Seeley and Woods, 2003; Lam et al., 2005a,b). Increased feeding by inhibition of fatty acid inhibition is hypothesized to send signals to the brain by vagal afferents. The brain plays an important role in the evaluation of energy status because the hypothalamus is the principal site that integrates signals from the periphery and other brain areas to regulate feeding behavior. The hypothalamus plays an important role in monitoring fatty acid metabolism as part of its energy-sensing function (Kim et al., 2002; Mobbs and Makimura, 2002; Obici et al., 2003). Fatty acids can be imported into the cell either from the blood circulation or synthesized de novo inside the cell. Within the cell, fatty acids either undergo oxidation in the mitochondria for energy production or may be directed towards glycerolipid synthesis (triglycerides or phospholipids) for later energy production or membrane function. In lipogenic tissues including liver and adipose, the fatty acid pathway is generally involved in the storage of excess energy in the form of triglycerides which can subsequently be oxidized to provide energy. Intracellularly, acetyl-CoA is the precursor for de novo synthesis of fatty acids. Acetyl-CoA carboxylase (ACC) catalyzes the conversion of acetyl-CoA to malonyl-CoA which is the basic unit for fatty acid synthesis by the enzyme fatty acid synthase (FAS) in the cytosol. To undergo mitochondrial oxidation, however, fatty acids must cross both the outer and inner mitochondrial membranes. This process is catalyzed by carnitine palmitoyltransferase-1 (CPT-1) which is bound to the outer mitochondrial membrane and subsequently by carnitine palmitoyltransferase-2 (CPT-2), an inner mitochondrial membrane enzyme. Two isoforms of ACC exist (ACC1 and ACC2) (Bianchi et al., 1990) with divergent functions for each and both isoforms are regulated by phosphorylation by 5′-adenosine monophosphate-activated kinase (AMPK), an energy-sensing enzyme. ACC1 (also known as ACC-α ) catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA. On the other hand, ACC2 (also known as ACC-β) colocalizes with CPT-1 and regulates mitochondrial fatty acid oxidation. Interestingly, malonyl-CoA is a potent inhibitor of CPT-1 (Ruderman et al., 2003) and has effects on both fatty acid oxidation in the mitochondria as well as the synthesis of various lipids. Disturbances in malonyl-CoA regulation may contribute to insulin resistance (Ruderman et al., 1999) and obesity (Ruderman et al., 1999; Loftus et al., 2000). ACC2-deficient mice accumulate less malonyl-CoA and show significant reduction in fat in adipose tissue, despite increased food intake, indicating that they were expending energy at an increased rate (Abu-Elheiga et al., 2003). ACC has been detected in select neurons of the brain, notably in the ARC of the hypothalamus (McGarry and Brown, 1997), although which ACC isoforms are present in these neurons, however, is not clear. ACC has also been detected in other brain cell types including astrocytes in culture (Blazquez et al., 1998) and oligodendrocytes (Spencer et al., 1993), but the relative contribution of each cell type to food intake is currently not known. Hypothalamic inhibition of CPT-1 decreases food intake and suppresses endogenous glucose production (Ruderman et al., 1999).

One important enzyme that plays a key role in cellular energy homeostasis, as mentioned previously, is AMPK (Hardie and Hawley, 2001). AMPK is an energy-sensing kinase, which responds to changes in the energy levels of the cell and the whole body in order to maintain adequate adenosine triphosphate (ATP) levels in the cell. AMPK phosphorylates and inactivates ACC, thereby inhibiting fatty acid synthesis by decreasing malonyl-CoA availability (Frederich and Balschi, 2002). AMPK immunostaining in mouse brain sections reveals a predominantly neuronal distribution although it is also detected in activated astrocytes (Turnley et al., 1999). Significant interactions exist between fatty acids and the endocrine system (Bhathena, 2000, 2006). Hypothalamic malonyl-CoA responds to the level of circulating glucose and leptin, both of which affect energy homeostasis (Wolfgang et al., 2007). Leptin decreases AMPK activity in the hypothalamus (Minokoshi et al., 2004). Intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMPK, activates ACC, the key regulatory enzyme in fatty acid biosynthesis, in the ARC and paraventricular nucleus (PVN) in the hypothalamus indicating that hypothalamic ACC activation makes an important contribution to leptin’s anorectic effects (Gao et al., 2007). Orexigenic hormones such as ghrelin and cannabinoids stimulate hypothalamic AMPK leading to an increase in appetite while inhibiting AMPK activity in the liver and adipose tissue, thereby leading to lipogenic effects (van Thuijl et al., 2008).

Pharmacological modulation of fatty acid metabolism has been utilized to inhibit food intake (Loftus et al., 2000). C75 (trans-4-carboxy-5-octyl-3-methylenebutyrolactone), originally designed as a FAS inhibitor (Kuhajda et al., 2000), causes profound, reversible weight loss in lean mice, diet-induced obese (DIO) mice, leptin-deficient (ob/ob) mice (Loftus et al., 2000; Thupari et al., 2004), and normal lean rats (Loftus et al., 2000). FAS inhibitors were initially developed as inhibitors of tumor progression, but these inhibitors also produced weight loss in mice (Loftus et al., 2000). ICV administration of C75 also rapidly suppresses food intake (Clegg et al., 2002; Aja et al., 2008). When administered peripherally, C75 decreases NPY/AgRP levels (Loftus et al., 2000) and increases POMC/CART levels in the brain (Thupari et al., 2004; Tu et al., 2005). In addition, ICV administration of ghrelin in mice blocks the inhibitor effects of C75 and decreases NPY levels and increases POMC/CART levels (Hu et al., 2005) indicating the interrelationship that exists between FAS inhibition and these neuropeptides. However, multiple distinct events related to fatty acid metabolism in the CNS coordinate energy balance as glucose, insulin, amino acids, leptin, and other metabolites all regulate FAS directly or indirectly (Semenkovich et al., 1993; Dudek and Semenkovich, 1995; Fukuda et al., 1999). One example is the recent report by Chakravarthy et al. (2007) who used a FAS knockout mouse with a genetic inactivation of FAS in the hypothalamus and pancreatic β cell. While these mice had less adiposity and decreased food intake (similar to what is observed with C75-treated animals), administration of a peroxisome proliferator-activated receptor-α (PPARα ) agonist into the hypothalamus increased PPARα target genes and normalized food intake. This is novel since PPARα is a transcription factor that is believed to respond to starvation, but is regulated by FAS, an enzyme that is activated by feeding. Such complexity only further highlights increased modulation that exists intracellularly in the fatty acid metabolic pathway in the brain to maintain energy balance. Figure 18.1 shows the interaction of some hormonal and neural pathways in the control of food intake.

FIGURE 18.1

Schematic of the neural regulation of food intake. Hypothalamus, in concert with brain stem and corticolimbic structures receives and integrates hormonal and metabolic signals from the periphery to regulate energy homeostasis. At the cellular level, acetyl-CoA (more...)

Cellular mechanisms by which fatty acids regulate neuronal activity are not clear, although their actions on ion channels in neurons as well as other cell types have been reported. Witt and Nielsen (2004) reported an increase in [³H]Diazepam-binding in rat cortex in vitro upon treatment with fatty acids indicating an influence on the γ-aminobutyric acid (GABA)/benzodiazepine receptor/Cl⁻ ion channel. Their effect on G protein-gated K⁺ channels by antagonizing the ATP-dependent gating in neurons and cardiac myocytes has also been reported (Kim and Pleumsamran, 2000). In gastric myocytes fatty acids markedly increase I_K(ca), a calcium-dependent potassium current, and the enhancing potencies were related to the number of double bonds in the fatty acid chain (Zheng et al., 2005). Hyperpolarization of rodent hepatocytes by palmitate has also been reported (Rossi and Scharrer, 1995; Rossi et al., 1995). Whether these mechanisms occur in the brain in the hypothalamus or in other neural centers that are involved in the regulation of food intake is not known.

Sensitivity to EFA is observed in the periphery in the control of obesity. As a percentage of total fatty acids, n – 3 EFA in liver and adipose tissue lipids were significantly lower in the obese mice than in the lean controls (Cunnane et al., 1985). Obese subjects have low EFA content in their circulating plasma lipids when compared to nonobese controls (Rössner et al., 1989). Serum and hepatic AA levels were elevated in obese compared to lean rats indicating abnormal arachidonate distribution in the obese Zucker rat (Phinney et al., 1993). A recent study reported that GLA reduced weight regain in humans following major weight loss (Schirmer and Phinney, 2007). While mechanisms underlying the effects of EFA in reducing obesity are not clear, LA significantly decreases adiponectin and leptin secretion, two adipokines known to influence weight gain and insulin sensitivity, in insulin-stimulated primary rat adipocytes (Pérez-Matute et al., 2007). Whether such a phenomenon occurs in the brain as well is not yet known.

18.3. ROLE OF FATTY ACIDS IN COGNITION

About 50%–60% of the dry weight of the brain consists of lipids and PUFAs constitute approximately 30% of the lipid content (Sastry, 1985). ω – 3 fatty acids including EPA and DHA play important roles in the development and maintenance of normal CNS structure and function. Chronic dietary intake of essential PUFAs may modulate learning and memory by being incorporated into neuronal plasma membranes. Representatives of two PUFA families, the ω – 3 and ω – 6 types become integrated into membrane phospholipids, where the actual (ω – 6)/(ω – 3) ratio is hypothesized to determine membrane fluidity and thus the function of membrane-bound proteins. Animal studies suggest that a deficiency of ω – 3 fatty acids may lead to behavioral or cognitive deficits (Bourre et al., 1989; Yehuda et al., 1999; Hichami et al., 2007). In addition, supplementation of DHA enhances cognitive function in both adult and old mice (Shirai and Suzuki, 2004). This study also reported an enhancement when DHA was supplemented with catechin, a dietary polyphenol. Whether polyphenols and ω – 3 fatty acids act at multiple independent sites to improve cognition is not known and should be investigated further. While DHA has beneficial effects, an increase in lipid peroxides formation is also a possibility (Halliwell, 1992) which may result in oxidative stress that could be harmful to normal brain (Yavin et al., 2002). Dietary sources especially rich in ω – 3 fatty acids include fish such as tuna, trout, and salmon as well as some plant oils which are a rich source of ALA.

DHA is a key component of neural and retinal membranes, and rapidly accumulates in the brain during gestation and the postnatal period. Long-chain ω – 3 fatty acids are thought to be important for fetal neurodevelopment. Positive associations have been shown between maternal intake of fish, seafood, and ω – 3 fatty acids during pregnancy and/or lactation and visual and cognitive development in human studies. Higher cord DHA concentration was associated with longer gestation, better visual acuity, and novelty preference on the Fagan Test at 6 months, and better Bayley Scale mental and psychomotor performance at 11 months. By contrast, DHA from breast-feeding was not related to any indicator of cognitive or motor development in this full-term sample (Jacobson et al., 2008). Despite encouraging results in human intervention studies (Oken et al., 2008; Olsen et al., 2008; Strain et al., 2008), several studies were unable to demonstrate a positive effect of prenatal ω – 3 supplementation (see Hadders-Algra, 2008 for review). Thus, limited evidence exists to support the notion that prenatal ω – 3 supplementation favors developmental outcome. Likewise, evidence for benefits of n – 3 long-chain PUFA on cognitive development in healthy children older than 2 years of age is too limited to allow a clear conclusion (Eilander et al., 2007). In adults, fatty fish and marine ω – 3 PUFA consumption was associated with a reduced risk of impaired cognitive function in a middle-aged population (Kalmijn et al., 2004). There was little evidence that the ω – 3 PUFAs were associated with cognitive change in an older population aged 65+ in the absence of any neurological disorder (Morris et al., 2005).

18.4. FATTY ACIDS IN NEUROLOGICAL DISORDERS

Deficiencies in ω – 3 fatty acids or an imbalance in the ratio of ω – 3 to ω – 6 fatty acids have been implicated in a variety of neurological disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), ischemic brain injury/stroke, and multiple sclerosis (MS) as well as psychiatric disorders. Neurons lack the enzymes for de novo synthesis of DHA and AA (Hardy and Higgins, 1992) and hence they are obtained from dietary sources or synthesized mainly in the liver from the dietary precursors ALA and LA. However, astrocytes produce DHA (Moore et al., 1991) some of which is likely exported to neurons although the mechanism by which fatty acids cross the plasma membrane to enter cells is not clear. A significant portion of studies have examined the role of DHA in neurological disorders.

18.5. SUMMARY AND PERSPECTIVES

Obesity is a global health problem with nearly 1 billion people categorized as obese. It is estimated that in the United States ~60% of the adult population and nearly 13% of children are obese or overweight. Obesity is often associated with, or considered a major risk factor for diabetes, cardiovascular diseases, stroke, and cancer, but now it is also recognized as a risk factor for AD, a progressive neurodegenerative disease. Obesity is also associated with declined cognitive function. Neural regulation of food intake is not only involved in behavior related to appetite but also in sensing the energy needs of the organism. The CNS including the hypothalamus, the brain stem, and the limbic system, with the help of autonomic nervous system, is sensitive to levels of metabolic and endocrine intermediates including glucose, fatty acids, insulin, and leptin that reflect peripheral energy status.

Both central and peripheral signals play important roles in regulating the complicated neuronal circuitry that regulates feeding and energy homeostasis. While much research into the role of fatty acids, based on in vivo and in vitro studies, have increased our knowledge, understanding their molecular mechanisms might provide new targets to prevent or attenuate obesity. Considering that multiple neural pathways function in concert to determine food intake, a more definitive role of how all these pathways relay information to one another and how various signaling molecules interact to eventually regulate energy homeostasis should permit a better understanding of appetite regulation. Furthermore, cellular mechanisms underlying the effects of fatty acids is not clear and should be investigated further in order to understand their effects on neural cells. While most studies have investigated the role of fatty acids on neurons, their effects on other cell types in the brain including astrocytes and oligodendrocytes are sparse. This would appear to be an important area of investigation since neuronal–astrocyte interactions are critical in determining the function of neurons especially since astrocytes provide energy substrates to neurons (see Panickar and Norenberg, 2005 for review). Further studies are also needed to examine the role of reward and cognition centers in the brain that modulate food intake. In addition, the function of orexigenic and anorexigenic peptides in the hippocampus to regulate appetite is not clear and needs further investigation. There is also evidence to indicate an important role for EFA in improving cognitive function and for neuroprotective effects of such are also appreciated, but more research and definitive data are required to reach conclusive answers.

ACKNOWLEDGMENTS

Supported by USDA CRIS Project # 1235-51520-037-00D and grant from Diabetes Action Research and Education Foundation.

ABBREVIATIONS

ACC

acetyl-CoA carboxylase

AD

Alzheimer’s disease

ALA

α-linolenic acid

AMPK

5′-adenosine monophosphate-activated protein kinase

AA

arachidonic acid

AgRP

agouti-related protein

ARC

arcuate nucleus

BBB

blood–brain barrier

CART

cocaine- and amphetamine-regulated transcript

CCK

cholecystokinin

CNS

central nervous system

CPT

carnitine palmitoyltransferase

DHA

docosahexanoic acid

DPA

docosapentaenoic acid

EFA

essential fatty acids

EPA

eicosapentaenoic acid

FA

fatty acids

FAS

fatty acid synthase

GLA

γ-linoleic acid

HD

Huntington’s disease

LA

linoleic acid

MS

multiple sclerosis

MSH

melanocyte-stimulating hormone

NPY

neuropeptide Y

NTS

nucleus of the solitary tract

PD

Parkinson’s disease

POMC

proopiomelanocortin

PUFA

polyunsaturated fatty acid

REFERENCES

1. Abu-Elheiga L, Oh W, Kordari P, Wakil SJ. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc Natl Acad Sci U S A. 2003;100(18):10207–10212. [PMC free article: PMC193540] [PubMed: 12920182]
2. Adan RA, Gispen WH. Brain melanocortin receptors: From cloning to function. Peptides. 1997;18:1279–1287. [PubMed: 9396074]
3. Aja S, Landree LE, Kleman AM, Medghalchi SM, Vadlamudi A, McFadden JM, Aplasca A, et al. Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight. Am J Physiol Regul Integr Comp Physiol. 2008;294(2):R352–R361. [PubMed: 18056987]
4. Anand BK, Brobeck JR. Hypothalamic control of food intake in rats and cats. Yale J Biol Med. 1951;24(2):123–40. [PMC free article: PMC2599116] [PubMed: 14901884]
5. Arendash GW, Jensen MT, Salem N Jr, Hussein N, Cracchiolo J, Dickson A, Leighty R, Potter H. A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer’s transgenic mice. Neuroscience. 2007;149(2):286–302. [PubMed: 17904756]
6. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest. 1967;46(10):1549–1557. [PMC free article: PMC292903] [PubMed: 6061732]
7. Bai F, Sözen MA, Lukiw WJ, Argyropoulos G. Expression of AgRP, NPY, POMC and CART in human fetal and adult hippocampus. Neuropeptides. 2005;39(4):439–443. [PubMed: 15885775]
8. Banks WA. The source of cerebral insulin. Eur J Pharmacol. 2004;490(1–3):5–12. [PubMed: 15094069]
9. Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides. 1996;17(2):305–311. [PubMed: 8801538]
10. Bas O, Songur A, Sahin O, Mollaoglu H, Ozen OA, Yaman M, Eser O, Fidan H, Yagmurca M. The protective effect of fish n-3 fatty acids on cerebral ischemia in rat hippocampus. Neurochem Int. 2007;50(3):548–554. [PubMed: 17187901]
11. Beglinger C. Overview: Cholecystokinin and eating. Curr Opin Invest Drugs. 2002;3(4):587–588. [PubMed: 12090729]
12. Berthoud HR. Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev. 2002;26(4):393–428. [PubMed: 12204189]
13. Bhathena SJ. Relationship between fatty acids and the endocrine system. Biofactors. 2000;13(1–4):35–39. [PubMed: 11237196]
14. Bhathena SJ. Relationship between fatty acids and the endocrine and neuroendocrine system. Nutr Neurosci. 2006;9(1–2):1–10. [PubMed: 16910164]
15. Bianchi A, Evans JL, Iverson AJ, Nordlund AC, Watts TD, Witters LA. Identification of an isozymic form of acetyl-CoA carboxylase. J Biol Chem. 1990;265(3):1502–1509. [PubMed: 1967254]
16. Blázquez C, Sánchez C, Velasco G, Guzmán M. Role of carnitine palmitoyltransferase I in the control of ketogenesis in primary cultures of rat astrocytes. J Neurochem. 1998;71(4):1597–1606. [PubMed: 9751193]
17. Bourre JM, Francois M, Youyou A, Dumont O, Piciotti M, Pascal G, Durand G. The effects of dietary alpha-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats. JNutr. 1989;119(12):1880–1892. [PubMed: 2576038]
18. Bousquet M, Saint-Pierre M, Julien C, Salem N Jr, Cicchetti F, Calon F. Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease. FASEB J. 2008;22(4):1213–1325. [PubMed: 18032633]
19. Brightman MW, Broadwell RD. The morphological approach to the study of normal and abnormal brain permeability. Adv Exp Med Biol. 1976;69:41–54. [PubMed: 60048]
20. Broberger C, Johansen J, Johansson C, Schalling M, Hökfelt T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci U S A. 1998;95(25):15043–15048. [PMC free article: PMC24572] [PubMed: 9844012]
21. Calder PC. n-3 polyunsaturated fatty acids and cytokine production in health and disease. Ann Nutr Metab. 1997;41(4):203–234. [PubMed: 9363294]
22. Calon F, Lim GP, Morihara T, Yang F, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer’s disease. Eur J Neurosci. 2005;22(3):617–626. [PubMed: 16101743]
23. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269(5223):546–549. [PubMed: 7624778]
24. Campfield LA, Smith FJ, Burn P. The OB protein (leptin) pathway—A link between adipose tissue mass and central neural networks. Horm Metab Res. 1996a;28(12):619–632. [PubMed: 9013731]
25. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. OB protein: A peripheral signal linking adiposity and central neural networks. Appetite. 1996b;26(3):302. [PubMed: 8800486]
26. Carlisle HJ, Reynolds RW. Effect of amphetamine on food intake in rats with brain-stem lesions. Am J Physiol. 1961;201:965–967. [PubMed: 13876613]
27. Chakravarthy MV, Zhu Y, López M, Yin L, Wozniak DF, Coleman T, Hu Z, et al. Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. J Clin Invest. 2007;117(9):2539–2552. [PMC free article: PMC1937501] [PubMed: 17694178]
28. Clegg DJ, Wortman MD, Benoit SC, McOsker CC, Seeley RJ. Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion. Diabetes. 2002;51(11):3196–3201. [PubMed: 12401710]
29. Clifford JJ, Drago J, Natoli AL, Wong JY, Kinsella A, Waddington JL, Vaddadi KS. Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease. Neuroscience. 2002;109(1):81–88. [PubMed: 11784701]
30. Coll AP, Farooqi IS, O’Rahilly S. The hormonal control of food intake. Cell. 2007;129(2):251–262. [PMC free article: PMC2202913] [PubMed: 17448988]
31. Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH. Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids. 2000;35(12):1305–1312. [PubMed: 11201991]
32. Cunnane SC, Manku MS, Horrobin DF. Essential fatty acids in the liver and adipose tissue of genetically obese mice: Effect of supplemental linoleic and gamma-linolenic acids. Br J Nutr. 1985;53(3):441–448. [PubMed: 2998443]
33. da Silva TM, Munhoz RP, Alvarez C, Naliwaiko K, Kiss A, Andreatini R, Ferraz AC. Depression in Parkinson’s disease: A double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J Affect Disord. 2008;111(2–3):351–359. [PubMed: 18485485]
34. Das UN. Is metabolic syndrome X a disorder of the brain with the initiation of low-grade systemic inflammatory events during the perinatal period? J Nutr Biochem. 2007;18(11):701–713. [PubMed: 17475465]
35. Das UN, Vaddadi KS. Essential fatty acids in Huntington’s disease. Nutrition. 2004;20(10):942–947. [PubMed: 15474886]
36. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000;141(11):4255–4261. [PubMed: 11089560]
37. de Lau LM, Schipper CM, Hofman A, Koudstaal PJ, Breteler MM. Prognosis of Parkinson disease: risk of dementia and mortality: The Rotterdam Study. Arch Neurol. 2005;62(8):1265–1269. [PubMed: 16087767]
38. Domingo JL. Omega-3 fatty acids and the benefits of fish consumption: Is all that glitters gold? Environ Int. 2007;33(7):993–998. [PubMed: 17540446]
39. Domingo JL, Bocio A, Falcó G, Llobet JM. Benefits and risks of fish consumption Part I. A quantitative analysis of the intake of omega-3 fatty acids and chemical contaminants. Toxicology. 2007a;230(2–3):219–226. [PubMed: 17161894]
40. Domingo JL, Bocio A, Martí-Cid R, Llobet JM. Benefits and risks of fish consumption. Part II. RIBEPEIX, a computer program to optimize the balance between the intake of omega-3 fatty acids and chemical contaminants. Toxicology. 2007b;230(2–3):227–233. [PubMed: 17178182]
41. Dudek SM, Semenkovich CF. Essential amino acids regulate fatty acid synthase expression through an uncharged transfer RNA-dependent mechanism. J Biol Chem. 1995;270:29323–29329. [PubMed: 7493965]
42. Eilander A, Hundscheid DC, Osendarp SJ, Transler C, Zock PL. Effects of n-3 long chain polyunsaturated fatty acid supplementation on visual and cognitive development throughout childhood: A review of human studies. Prostaglandins Leukot Essent Fatty Acids. 2007;76(4):189–203. [PubMed: 17376662]
43. Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB, Elmquist JK. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron. 1998;21(6):1375–1385. [PubMed: 9883730]
44. Frederich M, Balschi JA. The relationship between AMP-activated protein kinase activity and AMP concentration in the isolated perfused rat heart. J Biol Chem. 2002;277(3):1928–1932. [PubMed: 11707445]
45. Fukuda H, Iritani N, Sugimoto T, Ikeda H. Transcriptional regulation of fatty acid synthase gene by insulin/glucose, polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats. Eur J Biochem. 1999;260:505–511. [PubMed: 10095788]
46. Gallai V, Sarchielli P, Trequattrini A, Franceschini M, Floridi A, Firenze C, Alberti A, Di Benedetto D, Stragliotto E. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol. 1995;56(2):143–153. [PubMed: 7860710]
47. Gao S, Kinzig KP, Aja S, Scott KA, Keung W, Kelly S, Strynadka K, et al. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc Natl Acad Sci U S A. 2007;104(44):17358–17363. [PMC free article: PMC2077261] [PubMed: 17956983]
48. Gillette Guyonnet S, Abellan Van Kan G, Andrieu S, Barberger Gateau P, Berr C, Bonnefoy M, Dartigues JF, et al. IANA task force on nutrition and cognitive decline with aging. J Nutr Health Aging. 2007;11(2):132–152. [PubMed: 17435956]
49. Grossman SP, Grossman L. Food and water intake following lesions or electrical stimulation of the amygdala. Am J Physiol. 1963;205:761–765. [PubMed: 14060818]
50. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med. 2003;163(13):1524–1528. [PubMed: 12860573]
51. Haass C, Selkoe DJ. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell. 1993;75(6):1039–1042. [PubMed: 8261505]
52. Hadders-Algra M. Prenatal long-chain polyunsaturated fatty acid status: The importance of a balanced intake of docosahexaenoic acid and arachidonic acid. J Perinat Med. 2008;36(2):101–109. [PubMed: 18211254]
53. Hahn TM, Breininger JF, Baskin DG, Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci. 1998;11(4):271–272. [PubMed: 10195157]
54. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269(5223):543–546. [PubMed: 7624777]
55. Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem. 1992;59(5):1609–1623. [PubMed: 1402908]
56. Hardie DG, Hawley SA. AMP-activated protein kinase: The energy charge hypothesis revisited. Bioessays. 2001;23(12):1112–1119. [PubMed: 11746230]
57. Hardy JA, Higgins GA. Alzheimer’s disease: The amyloid cascade hypothesis. Science. 1992;256(5054):184–185. [PubMed: 1566067]
58. Härfstrand A, Fuxe K, Agnati LF, Benfenati F, Goldstein M. Receptor autoradiographical evidence for high densities of ¹²⁵I-neuropeptide Y binding sites in the nucleus tractus solitarius of the normal male rat. Acta Physiol Scand. 1986;128(2):195–200. [PubMed: 3022555]
59. Harper PS. Huntington’s Disease. W.B. Saunders; London: 1996.
60. Hashimoto M, Hossain S, Shimada T, Sugioka K, Yamasaki H, Fujii Y, Ishibashi Y, Oka J, Shido O. Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer’s disease model rats. J Neurochem. 2002;81(5):1084–1091. [PubMed: 12065621]
61. Hashimoto M, Tanabe Y, Fujii Y, Kikuta T, Shibata H, Shido O. Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused rats. J Nutr. 2005;135(3):549–555. [PubMed: 15735092]
62. Hashimoto M, Hossain S, Shimada T, Shido O. Docosahexaenoic acid-induced protective effect against impaired learning in amyloid beta-infused rats is associated with increased synaptosomal membrane fluidity. Clin Exp Pharmacol Physiol. 2006;33(10):934–939. [PubMed: 17002670]
63. Heurteaux C, Laigle C, Blondeau N, Jarretou G, Lazdunski M. Alpha-linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia. Neuroscience. 2006;137(1):241–251. [PubMed: 16289892]
64. Hichami A, Datiche F, Ullah S, Liénard F, Chardigny JM, Cattarelli M, Khan NA. Olfactory discrimination ability and brain expression of c-fos, Gir and Glut1 mRNA are altered in n-3 fatty acid-depleted rats. Behav Brain Res. 2007;184(1):1–10. [PubMed: 17686536]
65. Holman RT, Johnson SB, Kokmen E. Deficiencies of polyunsaturated fatty acids and replacement by nonessential fatty acids in plasma lipids in multiple sclerosis. Proc Natl Acad Sci U S A. 1989;86(12):4720–4724. [PMC free article: PMC287343] [PubMed: 2734316]
66. Hu Z, Cha SH, van Haasteren G, Wang J, Lane MD. Effect of centrally administered C75, a fatty acid synthase inhibitor, on ghrelin secretion and its downstream effects. Proc Natl Acad Sci U S A. 2005;102(11):3972–3977. [PMC free article: PMC549511] [PubMed: 15728730]
67. Hwa JJ, Ghibaudi L, Compton D, Fawzi AB, Strader CD. Intracerebroventricular injection of leptin increases thermogenesis and mobilizes fat metabolism in ob/ob mice. Horm Metab Res. 1996;28(12):659–663. [PubMed: 9013737]
68. Hwa JJ, Fawzi AB, Graziano MP, Ghibaudi L, Williams P, Van Heek M, Davis H, Rudinski M, Sybertz E, Strader CD. Leptin increases energy expenditure and selectively promotes fat metabolism in ob/ob mice. Am J Physiol. 1997;272(4 Pt 2):R1204–R1209. [PubMed: 9140021]
69. Ikeda H, West DB, Pustek JJ, Figlewicz DP, Greenwood MR, Porte D Jr, Woods SC. Intraventricular insulin reduces food intake and body weight of lean but not obese Zucker rats. Appetite. 1986;7(4):381–386. [PubMed: 3539015]
70. Iso H, Rexrode KM, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Hennekens CH, Willett WC. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001;285(3):304–312. [PubMed: 11176840]
71. Jacobson JL, Jacobson SW, Muckle G, Kaplan-Estrin M, Ayotte P, Dewailly E. Beneficial effects of a polyunsaturated fatty acid on infant development: Evidence from the Inuit of arctic Quebec. J Pediatr. 2008;152(3):356–364. [PubMed: 18280840]
72. Kalmijn S, van Boxtel MP, Ocké M, Verschuren WM, Kromhout D, Launer LJ. Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurology. 2004;62(2):275–280. [PubMed: 14745067]
73. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev. 1999;20(1):68–100. [PubMed: 10047974]
74. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci. 1953;40(901):578–596. [PubMed: 13027283]
75. Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol. 1985;42:1097–1105. [PubMed: 2864910]
76. Kim D, Pleumsamran A. Cytoplasmic unsaturated free fatty acids inhibit ATP-dependent gating of the G protein-gated K⁺ channel. J Gen Physiol. 2000;115(3):287–304. [PMC free article: PMC2217204] [PubMed: 10694258]
77. Kim EK, Miller I, Landree LE, Borisy-Rudin FF, Brown P, Tihan T, Townsend CA, et al. Expression of FAS within hypothalamic neurons: A model for decreased food intake after C75 treatment. Am J Physiol Endocrinol Metab. 2002;283(5):E867–E879. [PubMed: 12376313]
78. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660. [PubMed: 10604470]
79. Koyama K, Chen G, Wang MY, Lee Y, Shimabukuro M, Newgard CB, Unger RH. Beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. Diabetes. 1997;46(8):1276–1280. [PubMed: 9231651]
80. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature. 1998;393(6680):72–76. [PubMed: 9590691]
81. Kuhajda FP, Pizer ES, Li JN, Mani NS, Frehywot GL, Townsend CA. Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc Natl Acad Sci U S A. 2000;97(7):3450–3454. [PMC free article: PMC16260] [PubMed: 10716717]
82. Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005a;11(3):320–327. [PubMed: 15735652]
83. Lam TK, Schwartz GJ, Rossetti L. Hypothalamic sensing of fatty acids. Nat Neurosci. 2005b;8(5):579–584. [PubMed: 15856066]
84. Lang-Lazdunski L, Blondeau N, Jarretou G, Lazdunski M, Heurteaux C. Linolenic acid prevents neuronal cell death and paraplegia after transient spinal cord ischemia in rats. J Vasc Surg. 2003;38(3):564–575. [PubMed: 12947278]
85. Lauritzen I, Blondeau N, Heurteaux C, Widmann C, Romey G, Lazdunski M. Polyunsaturated fatty acids are potent neuroprotectors. EMBO J. 2000;19(8):1784–1793. [PMC free article: PMC302016] [PubMed: 10775263]
86. Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell AA. Neuronal gluco-sensing: What do we know after 50 years? Diabetes. 2004;53(10):2521–2528. [PubMed: 15448079]
87. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25(12):3032–3040. [PMC free article: PMC6725084] [PubMed: 15788759]
88. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288(5475):2379–2381. [PubMed: 10875926]
89. Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM. Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer’s disease (AD): Relevance to AD prevention. J Neurosci. 2007;27(52):14299–14307. [PMC free article: PMC2628584] [PubMed: 18160637]
90. Mayer J. Glucostatic mechanism of regulation of food intake. N Engl J Med. 1953;249(1):13–16. [PubMed: 13063674]
91. Mayer J. Regulation of energy intake and the body weight: The glucostatic theory and the lipostatic hypothesis. Ann N Y Acad Sci. 1955;63(1):15–43. [PubMed: 13249313]
92. Mayer J. Glucostatic mechanism of regulation of food intake. 1953. Obes Res. 1996;4(5):493–496. [PubMed: 8885216]
93. McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997;244(1):1–14. [PubMed: 9063439]
94. Menéndez JA, Atrens DM. Insulin and the paraventricular hypothalamus: modulation of energy balance. Brain Res. 1991;555(2):193–201. [PubMed: 1933333]
95. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428(6982):569–574. [PubMed: 15058305]
96. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology. 1991;41:479–486. [PubMed: 2011243]
97. Mobbs CV, Makimura H. Block the FAS, lose the fat. Nat Med. 2002;8(4):335–336. [PubMed: 11927935]
98. Moore SA, Yoder E, Murphy S, Dutton GR, Spector AA. Astrocytes, not neurons, produce docosahexaenoic acid (22:6 omega-3) and arachidonic acid (20:4 omega-6). J Neurochem. 1991;56(2):518–524. [PubMed: 1824862]
99. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Fish consumption and cognitive decline with age in a large community study. Arch Neurol. 2005;62(12):1849–1853. [PubMed: 16216930]
100. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol. 1994;8:1298–1308. [PubMed: 7854347]
101. Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9(6):756–761. [PubMed: 12754501]
102. Okada M, Amamoto T, Tomonaga M, Kawachi A, Yazawa K, Mine K, Fujiwara M. The chronic administration of docosahexaenoic acid reduces the spatial cognitive deficit following transient forebrain ischemia in rats. Neuroscience. 1996;71(1):17–25. [PubMed: 8834389]
103. Oken E, Radesky JS, Wright RO, Bellinger DC, Amarasiriwardena CJ, Kleinman KP, Hu H, Gillman MW. Maternal fish intake during pregnancy, blood mercury levels, and child cognition at age 3 years in a US cohort. Am J Epidemiol. 2008;167(10):1171–1181. [PMC free article: PMC2590872] [PubMed: 18353804]
104. Olsen SF, Østerdal ML, Salvig JD, Mortensen LM, Rytter D, Secher NJ, Henriksen TB. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88(1):167–175. [PubMed: 18614738]
105. Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschöp M. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol. 2001;145(5):669–673. [PubMed: 11720888]
106. Ozen OA, Cosar M, Sahin O, Fidan H, Eser O, Mollaoglu H, Alkoc O, Yaman M, Songur A. The protective effect of fish n-3 fatty acids on cerebral ischemia in rat prefrontal cortex. Neurol Sci. 2008;29(3):147–152. [PubMed: 18612761]
107. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1–2):359–378. [PubMed: 8958163]
108. Panickar KS, Norenberg MD. Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia. 2005;50(4):287–298. [PubMed: 15846806]
109. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269(5223):540–543. [PubMed: 7624776]
110. Pérez-Matute P, Martínez JA, Marti A, Moreno-Aliaga MJ. Linoleic acid decreases leptin and adiponectin secretion from primary rat adipocytes in the presence of insulin. Lipids. 2007;42(10):913–920. [PubMed: 17647039]
111. Phinney SD, Tang AB, Thurmond DC, Nakamura MT, Stern JS. Abnormal polyunsaturated lipid metabolism in the obese Zucker rat, with partial metabolic correction by gamma-linolenic acid administration. Metabolism. 1993;42(9):1127–1140. [PubMed: 8412765]
112. Pomponi M, Pomponi M. DHA deficiency and Alzheimer’s disease. Clin Nutr. 2008;27(1):170. [PubMed: 18037538]
113. Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot Essent Fatty Acids. 2007;77(5–6):251–261. [PMC free article: PMC2725409] [PubMed: 18060754]
114. Relton JK, Strijbos PJ, Cooper AL, Rothwell NJ. Dietary N-3 fatty acids inhibit ischaemic and excitotoxic brain damage in the rat. Brain Res Bull. 1993;32(3):223–226. [PubMed: 8374800]
115. Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res. 1978;153(1):1–26. [PubMed: 679038]
116. Rossi R, Scharrer E. Hyperpolarization of the liver cell membrane by palmitate as affected by glucose and lactate: Implications for control of feeding. J Auton Nerv Syst. 1995;56(1–2):45–49. [PubMed: 8786279]
117. Rossi R, Geronimi M, Gloor P, Seebacher MC, Scharrer E. Hyperpolarization of the cell membrane of mouse hepatocytes by fatty acid oxidation. Physiol Behav. 1995;57(3):509–514. [PubMed: 7753889]
118. Rössner S, Walldius G, Björvell H. Fatty acid composition in serum lipids and adipose tissue in severe obesity before and after six weeks of weight loss. Int J Obes. 1989;13(5):603–612. [PubMed: 2583914]
119. Ruderman NB, Saha AK, Vavvas D, Witters LA. Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol. 1999;276(1 Pt 1):E1–E18. [PubMed: 9886945]
120. Ruderman NB, Saha AK, Kraegen EW. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology. 2003;144(12):5166–5171. [PubMed: 14500570]
121. Samadi P, Grégoire L, Rouillard C, Bédard PJ, Di Paolo T, Lévesque D. Docosahexaenoic acid reduces levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys. Ann Neurol. 2006;59(2):282–288. [PubMed: 16437566]
122. Sastry PS. Lipids of nervous tissue: composition and metabolism. Prog Lipid Res. 1985;24(2):69–176. [PubMed: 3916238]
123. Sawchenko PE, Swanson LW, Grzanna R, Howe PR, Bloom SR, Polak JM. Colocalization of neuropeptide Y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus. J Comp Neurol. 1985;241(2):138–153. [PubMed: 3840810]
124. Schirmer MA, Phinney SD. Gamma-linolenate reduces weight regain in formerly obese humans. J Nutr. 2007;137(6):1430–1435. [PubMed: 17513402]
125. Seeley RJ, Woods SC. Monitoring of stored and available fuel by the CNS: implications for obesity. Nat Rev Neurosci. 2003;4(11):901–909. [PubMed: 14595401]
126. Semenkovich CF, Coleman T, Goforth R. Physiologic concentrations of glucose regulate fatty acid synthase activity in HepG2 cells by mediating fatty acid synthase mRNA stability. J Biol Chem. 1993;268:6961–6970. [PubMed: 8463228]
127. Sergeeva M, Strokin M, Reiser G. Regulation of intracellular calcium levels by polyunsaturated fatty acids, arachidonic acid and docosahexaenoic acid, in astrocytes: possible involvement of phospholipase A2. Reprod Nutr Dev. 2005;45(5):633–646. [PubMed: 16188212]
128. Shimabukuro M, Koyama K, Chen G, Wang MY, Trieu F, Lee Y, Newgard CB, Unger RH. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A. 1997;94(9):4637–4641. [PMC free article: PMC20776] [PubMed: 9114043]
129. Shirai N, Suzuki H. Effect of dietary docosahexaenoic acid and catechins on maze behavior in mice. Ann Nutr Metab. 2004;48(1):51–58. [PubMed: 14646341]
130. Skinner ER, Watt C, Besson JA, Best PV. Differences in the fatty acid composition of the grey and white matter of different regions of the brains of patients with Alzheimer’s disease and control subjects. Brain. 1993;116(Pt 3):717–725. [PubMed: 8513399]
131. Söderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids. 1991;26(6):421–425. [PubMed: 1881238]
132. Spencer EB, Bianchi A, Widmer J, Witters LA. Brain acetyl-CoA carboxylase: isozymic identification and studies of its regulation during development and altered nutrition. Biochem Biophys Res Commun. 1993;192(2):820–825. [PubMed: 8097913]
133. Stellar E. The physiology of motivation. Psychol Rev. 1954;61(1):5–22. [PubMed: 13134413]
134. Stephens TW, Margret Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 1995;377(6549):530–532. [PubMed: 7566151]
135. Stillwell W, Wassall SR. Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids. 2003;126(1):1–27. [PubMed: 14580707]
136. Stoeckel LE, Weller RE, Cook EW 3rd, Twieg DB, Knowlton RC, Cox JE. Widespread reward-system activation in obese women in response to pictures of high-calorie foods. Neuroimage. 2008;41(2):636–647. [PubMed: 18413289]
137. Strain JJ, Davidson PW, Bonham MP, Duffy EM, Stokes-Riner A, Thurston SW, Wallace JM, et al. Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study. Neurotoxicology. 2008;29(5):776–782. [PMC free article: PMC2574624] [PubMed: 18590765]
138. Strubbe JH, Mein CG. Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiol Behav. 1977;19(2):309–313. [PubMed: 607241]
139. Swank RL, Lerstad O, Strøm A, Backer J. Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N Engl J Med. 1952;246(19):722–728. [PubMed: 14929306]
140. Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S. Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology. 2002;143(9):3268–3275. [PubMed: 12193538]
141. Tanaka K, Ishikawa Y, Yokoyama M, Origasa H, Matsuzaki M, Saito Y, Matsuzawa Y, et al. JELIS Investigators, Japan. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: Subanalysis of the JELIS trial. Stroke. 2008;39(7):2052–2058. [PubMed: 18451347]
142. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83(7):1263–1271. [PubMed: 8548812]
143. Thupari JN, Kim EK, Moran TH, Ronnett GV, Kuhajda FP. Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass. Am J Physiol Endocrinol Metab. 2004;287(1):E97–E104. [PubMed: 14736702]
144. Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–913. [PubMed: 11057670]
145. Tu Y, Thupari JN, Kim EK, Pinn ML, Moran TH, Ronnett GV, Kuhajda FP. C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure. Endocrinology. 2005;146(1):486–493. [PubMed: 15498887]
146. Tully AM, Roche HM, Doyle R, Fallon C, Bruce I, Lawlor B, Coakley D, Gibney MJ. Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer’s disease: A case–control study. Br J Nutr. 2003;89(4):483–489. [PubMed: 12654166]
147. Turnley AM, Stapleton D, Mann RJ, Witters LA, Kemp BE, Bartlett PF. Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J Neurochem. 1999;72(4):1707–1716. [PubMed: 10098881]
148. Vaddadi KS, Soosai E, Chiu E, Dingjan P. A randomised, placebo-controlled, double blind study of treatment of Huntington’s disease with unsaturated fatty acids. Neuroreport. 2002;13(1):29–33. [PubMed: 11924889]
149. van Thuijl H, Kola B, Korbonits M. Appetite and metabolic effects of ghrelin and cannabinoids: Involvement of AMP-activated protein kinase. Vitam Horm. 2008;77:121–148. [PubMed: 17983855]
150. Wang GJ, Yang J, Volkow ND, Telang F, Ma Y, Zhu W, Wong CT, Tomasi D, Thanos PK, Fowler JS. Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry. Proc Natl Acad Sci U S A. 2006;103(42):15641–15645. [PMC free article: PMC1592230] [PubMed: 17023542]
151. Wennberg M, Bergdahl IA, Stegmayr B, Hallmans G, Lundh T, Skerfving S, Strömberg U, Vessby B, Jansson JH. Fish intake, mercury, long-chain n-3 polyunsaturated fatty acids and risk of stroke in northern Sweden. Br J Nutr. 2007;98(5):1038–1045. [PubMed: 17537290]
152. Witt MR, Nielsen M. Characterization of the influence of unsaturated free fatty acids on brain GABA/benzodiazepine receptor binding in vitro. J Neurochem. 1994;62(4):1432–1439. [PubMed: 8133272]
153. Wolfgang MJ, Cha SH, Sidhaye A, Chohnan S, Cline G, Shulman GI, Lane MD. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc Natl Acad Sci U S A. 2007;104(49):19285–19290. [PMC free article: PMC2148282] [PubMed: 18032600]
154. Woods SC, Lotter EC, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282(5738):503–505. [PubMed: 116135]
155. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001a;86(12):5992–5995. [PubMed: 11739476]
156. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 2001b;50(11):2540–2547. [PubMed: 11679432]
157. Wu Y, Tada M, Takahata K, Tomizawa K, Matsui H. Inhibitory effect of polyunsaturated fatty acids on apoptosis induced by etoposide, okadaic acid and AraC in Neuro2a cells. Acta Med Okayama. 2007;61(3):147–152. [PubMed: 17593950]
158. Xu L, Sun X, Lu J, Tang M, Chen JD. Effects of gastric electric stimulation on gastric distention responsive neurons and expressions of CCK in rodent hippocampus. Obesity (Silver Spring). 2008;16(5):951–957. [PubMed: 18309302]
159. Yavin E, Brand A, Green P. Docosahexaenoic acid abundance in the brain: a biodevice to combat oxidative stress. Nut Neurosci. 2002;5:149–157. [PubMed: 12041873]
160. Yehuda S, Rabinovitz S, Mostofsky DI. Essential fatty acids are mediators of brain biochemistry and cognitive functions. J Neurosci Res. 1999;56(6):565–570. [PubMed: 10374811]
161. Zheng HF, Li XL, Jin ZY, Sun JB, Li ZL, Xu WX. Effects of unsaturated fatty acids on calcium-activated potassium current in gastric myocytes of guinea pigs. World J Gastroenterol. 2005;11(5):672–675. [PMC free article: PMC4250736] [PubMed: 15655819]

Footnotes

*

This chapter is dedicated to the memory of Dr. Sam Bhathena, an eminent scientist at the USDA, who passed away during the preparation of this manuscript.