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Montmayeur JP, le Coutre J, editors. Fat Detection: Taste, Texture, and Post Ingestive Effects. Boca Raton (FL): CRC Press/Taylor & Francis; 2010.

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Fat Detection: Taste, Texture, and Post Ingestive Effects.

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Chapter 16Heritable Variation in Fat Preference

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16.1. INTRODUCTION

For humans, eating is often a group rather than a solitary activity, and it is inevitable when eating with others that individual differences in food preferences become obvious. These food preferences form early in life (Mennella et al., 2001) and persist into adulthood (Nicklaus et al., 2004). People like to eat familiar foods that are safe and avoid foods associated, even indirectly, with illness. However, pleasant experiences and time also help to form food preferences. For instance, the ability to tolerate and even like bitterness increases as children grow to adulthood, and the liking for sweet and sour decreases (Desor and Beauchamp, 1987; Liem and Mennella, 2003). Over a lifetime, new foods are tried, rejected, or incorporated into the diet. Against this backdrop of development and environment, there are inborn differences in food likes and dislikes which may be due to genetic constitution. There is a genetic basis to bitter detection in humans (Bufe et al., 2005) and given that fat intake is moderately to highly heritable, it is likely that genotype contributes to food selection and, by extension, to fat preference.

The focus here is on how individual differences in fat preference are formed and, in particular, the evidence that the liking for fat is influenced by genotype. The interest in dietary fat arises because its intake is tied to metabolic syndrome, a constellation of disorders that feature obesity, diabetes, and hypertension. An adage is that everything that tastes good is bad for you, and the liking for fat fits well into this viewpoint: fat is desirable and when people are given the opportunity to do so, many will adopt a high-fat diet. Two aspects of fat make it attractive, its sensory qualities (Reed et al., 1992b) and postingestive consequences (i.e., feelings of satiety). Fat is sensed in the mouth and although the texture is a key feature of its sensory properties, fat itself may be a legitimate taste stimulus. The evidence for this assertion is recent and reviewed below, but it is useful to know that fat has been considered a taste by some through the ages. For instance, Fernel wrote “There are nine classes of flavors, and the sense of taste recognizes no others: acrid, tart, fatty; salty, sour, and sweet; bitter, pungent, and insipid” (Fernelius, 1581). While controversies arise when applying the term “taste” to fat, and the issue is dealt with elsewhere in this book, “umami” as a taste was equally controversial but it was readily adopted as a fifth basic taste once the receptor(s) was identified (Chaudhari et al., 2000; Nelson et al., 2002). Likewise, when the oral receptors for fat are unequivocally identified, its place as a basic taste will probably become equally well accepted. What is known about fat as a taste is outlined below.

Taste is both the gatekeeper and advance messenger of ingestion, keeping out bad food and warning the gastrointestinal system about the impending rush of nutrients. One of the effects of fat stimuli in the mouth is to prepare the body for calories, setting off a cephalic phase response. This cascade of events may be a general response to incoming dietary fat in mammals because it is found in rats (Ramirez, 1985) as well as people (Mattes, 2001; Crystal and Teff, 2006). Under normal circumstances, once fat is ingested, it is briefly held in the stomach and then absorbed in the intestines. From here it is either oxidized for energy or stored, primarily in adipose tissue. In some abnormal states, such as untreated diabetes, fat is more easily oxidized than carbohydrate and is thus preferred, at least in experiments using animal models (Tordoff et al., 1987). In addition to the other benefits of fat, it contains pharmacologically active substances, for instance, olive oil has an anti-inflammatory agent (Beauchamp et al., 2005). These compounds may also contribute to the human liking for fat.

16.2. FAT AS A TASTE QUALITY

The details of how fat is sensed in the mouth are not well understood but it is worth reviewing what is currently known to help put the potential for genetic influences into perspective. The chemical properties of fat (as opposed to its texture) are probably sensed after it is hydrolyzed to free fatty acids rather than sensed as triglycerides. This conclusion is drawn from a study in rats which demonstrated that when lingual lipase (the oral enzyme responsible for breaking down triglyceride to free fatty acids) is reduced, triglycerides become less preferred while the preference for free fatty acids remain unchanged (Kawai and Fushiki, 2003). There is a belief that humans do not have as much lingual lipase as rats (Pritchard et al., 1967) and therefore probably do not rely on fat “taste” to the same extent, but this widely held belief is due for reconsideration, perhaps using other methods to measure lingual lipase, such as proteomics. From rat studies, we know that lingual lipase acts quickly on the tongue to liberate free fatty acids but if oral fat perception requires an enzymatic step, it may explain why fat-containing foods are often savored. Perhaps, keeping the fat-containing food in the mouth for a few extra seconds enhances its enjoyment. Lingual lipase is also most highly concentrated around the circumvallate papillae (in the rear of the mouth) and so the path to fat perception may start there (Hamosh and Scow, 1973). Although the majority of studies on oral free fatty acid detection are done using rats and mice as experimental subjects, humans can detect them in solution, and people differ markedly in their threshold and perceptions of intensity for free fatty acids (Chale-Rush et al., 2007a).

How are free fatty acids sensed in the mouth so that information about their presence can be relayed to the brain? The current hypothesis is that they are sensed in the same way that some other tastes are sensed in the mouth, i.e., they are detected by G-protein-coupled receptors (GPCRs) in taste receptor cells on the tongue, which in turn signal through a common second-messenger cascade involving G-proteins, phospholipase C beta2, and the transient receptor potential M5 (TRPM5) ion channel. This signal is then relayed to the brain by gustatory nerves and decoded.

Many lines of evidence support this model of fat perception. Investigators have recorded from or cut the gustatory nerves (as opposed to trigeminal sensory nerves) and demonstrated that information about the presence of fat in the mouth is conveyed to the brain (Stratford et al., 2006; Gaillard et al., 2007; Stratford et al., 2008). Furthermore, free fatty acids elicit an increase in intracellular calcium in about 30% of rat taste receptor cells (Liu et al., 2008a) and this event is associated with cell signaling through the release of neurotransmitters. In addition, several GPCRs have been suggested to be the “fat taste receptor”: one such is GPR120, which is expressed in taste tissue but not nonsensory epithelium (Cartoni et al., 2007; Tsuzuki, 2007; Matsumura et al., 2008). When introduced into a cell-based assay, GPR120 causes the cell to respond to fatty acids by increasing intracellular calcium (Tsuzuki, 2007; Eguchi, 2008), similar to the response seen by other GPCRs specific to classic taste stimuli (Adler et al., 2000; Chandrashekar et al., 2000; Nelson et al., 2001, 2002). GPR40 has also been implicated in fat taste but this finding is controversial; some investigators find that receptor is expressed in taste receptor cells (Cartoni et al., 2007) while others do not (Matsumura et al., 2008). However, mice genetically engineered to be null for this receptor (GPR40) have reduced preferences for fats like corn oil, which supports the role of this receptor in oral fat perception (although this effect could also come from other tissues since GPR40 is also expressed in pancreatic β cells) (Itoh et al., 2003).

Another membrane-bound protein that is related to fat taste is CD36. Several lines of evidence support its role in taste: (a) it is detected at the apical surface of taste receptor cells (where chemical stimuli in the mouth and receptors would interact), (b) it colocalizes in taste papillae with known signaling molecules (Laugerette et al., 2005), (c) the normal increase in intracellular calcium of taste receptor cells in response to free fatty acids is blocked in CD36 knockout mice, and (d) the activation of brain areas associated with fatty acid stimulation is eliminated in these knockout mice (Gaillard et al., 2007). Furthermore, (e) CD36 knockout mice are indifferent to fat solutions that mice with intact alleles prefer (Fushiki and Kawai, 2005; Laugerette et al., 2005; Sclafani et al., 2007a). However, CD36 and GPR120 are not often found in the same taste receptor cells (Matsumura et al., 2008), so whether they reflect two mechanisms of fat sensing or work together through cell-to-cell signaling is not known. There are a few more available pieces of information about the signaling cascade involved in fatty acid perception. Gustducin (a G-protein found in taste receptor cells) does not seem to be involved in fat taste because knockout of this gene does not affect fat preference in mice (Sclafani et al., 2007a,b). However, the transient receptor potential cation channel found in taste cells (TRPM5) is important in fat perception because knockout of this gene abolishes fat intake (Sclafani et al., 2007a,b). Taken together, free fatty acids are detected in taste receptor cells, and this information is conveyed through gustatory nerves where the information is interpreted by the brain. Although several genes and their associated proteins involved in the transduction pathway have been identified, the details are not well understood. However, the genes that are known to be involved are polymorphic in humans (see “Electronic Resources”), and therefore, alleles of these receptors and other signaling molecules would be a natural target of genetic investigation.

16.3. ANIMAL MODELS OF FAT PREFERENCE

A brief review of the advances in knowledge through animal research will be helpful in interpreting the human studies. Research on fat preferences has focused on mice and rats, mostly because they are commensal with humans and have similar food preferences. In fact, one way to make mice and rats fat is to feed them human “junk-food” (Sclafani and Springer, 1976), which is typically high in fat. However, research in the area of taste and food preferences is developing using flies and worms as model systems and these approaches will also add to our knowledge of the molecular aspects of fat preference (Gordesky-Gold et al., 2008). One of the important messages from animal research is the power of both genetics and experience to change fat preference. Rats given a sample of pure fat to eat for several days later select a diet very high in fat when offered a choice between fat, protein, and carbohydrate (Reed et al., 1992a,b). Rats offered only a high-fat diet become avid fat consumers and will drink large amounts of pure oil (Reed et al., 1991). Although these experiments demonstrate the power of experience on fat preference, the results of genetic studies have also reinforced the point that fat preference is inborn. Inbred strains of rats and mice treated similarly differ markedly in their willingness to ingest fat and they also differ in how much weight they gain when they do (Schemmel et al., 1970; West et al., 1992; Lewis et al., 2007; Svenson et al., 2007). Specific strains have been identified and studied because of their disparate fat preference or response to a high-fat diet (West et al., 1995; Levin et al., 1997; Smith Richards et al., 2002; Almind and Kahn, 2004; Collins et al., 2004; Ehrich et al., 2005; Kumar et al., 2007; Svenson et al., 2007; Tordoff et al., 2008).

With the advent of new methods in molecular genetics, it is possible to identify the specific genes that contribute to individual differences among mice (and humans, see below) in fat preference. One such study was conducted by crossing inbred strains of mice that had either a high- or low-fat preference, and evaluating the offspring for macronutrient preference. By comparing the parents, grandparents, and offspring from three generations, the genetic effects on fat preference could be established (h2 = 0.19) (Smith Richards et al., 2002), an estimate strikingly similar to the heritability of fat preference in humans (see below). The investigators conducted a genome-wide scan and found three chromosomal regions where fat-preferring mice shared DNA in common more often than could be expected by chance. These loci were on chromosomes 8 and 18, and also on the X-chromosome. The genes that contribute to the fat preference within these regions are not known, but this landmark study demonstrates that specific genetic regions are associated with fat preference and that it may be possible soon to identify the specific genes involved. This work is likely to advance further, because one of the benefits to studying model systems for fat preference is the tighter control over experience and learning and the wealth of molecular resources, e.g., genetic engineering, microarray, proteomics, and breeding techniques available.

16.4. HUMAN FAT PREFERENCE

Animal models are useful because they may point the way to understand human behavior toward high-fat foods. The study of fat preference in animal models is simpler than for humans because it is assumed that when animals are offered a choice, the item selected is the one preferred. However, this is not the case in humans, who are motivated by complex thoughts and constraints such as health beliefs, price, advertising, and social embarrassment. To make the problem even harder, humans are faced with multiple choices and rarely encounter the simple two-food choice offered to rats or mice. Therefore, to understand fat preference in humans, it is important to explicitly consider how it is measured and the limitations of these methods. This issue of measurement is also of particular concern for genetic studies because accurate estimates of heritability and genotype–phenotype associations depend upon the ability to assess a large number of people using methods that detect stable individual differences, and thus, even the most rudimentary measures in a controlled laboratory study are often out of reach.

16.5. METHODS OF MEASURING FAT PREFERENCE

Because of the impracticality of testing thousands of people in the lab, most genetic studies have relied on self-reported fat intake as a proxy measure of fat preference, with the expectation that in the broadest terms, people eat more of the food they prefer. A common way to collect data is through food diaries, in which the subject tracks food intake. Advantages of this method are that it is readily available, the subject is in their habitual environment and eating as usual—or nearly so, because there will be effects of recordkeeping on food intake. The limitation is that even for subjects who are motivated and honest in their reports, errors are introduced because of estimates of food composition or portion size, and there is also the risk that subjects may try to mislead the investigator by failing to record foods that are undesirable. The underreporting of food intake by the diary method is a well-known and often studied phenomenon, and to make matters worse in the realm of fat preference, these types of foods are sometimes selectively underreported (Goris et al., 2000). To circumvent this bias, creative investigators have tried to reduce recording errors, by asking subjects to photograph their meals immediately before they are eaten (de Castro, 2000). Another pencil and paper method to assess food intake is through food frequency questionnaires, which require that subjects recall their food intake and give information about how many times they have consumed a certain food during the past. The benefit of this method is that the time spent in collecting data is reduced and in contrast to food diaries, it does not rely on a subject’s sustained attention and continuous participation. The disadvantage is that this method is a less sensitive way to measure food intake.

Another way to measure human food intake is to have subjects live in structured environments in which their food choices and intake can be monitored more precisely—these types of studies can be conducted in a cafeteria where subjects come for meal time (Levitsky and Youn, 2004), a restaurant (Wansink et al., 2007), or in environments where subjects come to live (for short periods of time) so that their food intake can be closely monitored (Larson et al., 1995). Another method to measure fat intake and preference is to invite subjects into the laboratory and give them an opportunity to select food for a single meal or to ask subjects to taste and rate foods that differ in fat content (Mela and Sacchetti, 1991). The advantage of these types of laboratory studies is that the amount and type of food consumed can be more accurately monitored, but the limitation is that the subjects’ eating behavior is unlikely to be the same as it would be were the subjects living in their normal environment. The benefit of these short-term laboratory-based methods is that they can be tailored to ask specific research questions, but there are limitations because short-term tests are less likely to generalize to food preferences and intake outside of the laboratory (Pangborn and Giovanni, 1984). Furthermore, subjects are not adept at discerning the fat content of food in short-term tests (Mela and Christensen, 1987).

16.6. FAT PREFERENCE AS A HERITABLE HUMAN TRAIT

With these limitations in mind, the liking for a diet high or low in fat may be a stable trait (phenotype) of human subjects (Geiselman et al., 1998; Blundell and Cooling, 1999) and identifying a stable trait is the first step in establishing heritability. However, it is surprisingly rare for investigators to include reliability data in food preference studies with a genetic focus. Therefore, the genetic studies reviewed below need to be evaluated in this context: although fat preference may be a stable individual trait, methods to assess it are imperfect and thus, true heritability may be higher than reported due to measurement errors in the methods used to assess fat preference. It is also important to remember that exposure, experience, learning, and culture shape fat preference. Studies in rats suggest that maternal exposure to a high-fat diet results in offspring or even grandchildren that have an increased fat preference (Wu and Suzuki, 2006; Bayol et al., 2007). Other studies have suggested that maternal diet can affect the methylation of gene promoters which can in turn change gene regulation in the offspring (Waterland and Jirtle, 2003; Burdge et al., 2007). Given these observations, it is a short step to speculate that women who eat a high-fat diet during pregnancy and lactation might pass this trait on to their offspring through epigenetic mechanisms. In addition to exposure during development, fat preference may be due in part to cultural learning and the most obvious example is the changes that occur when people immigrate. However, something as simple as an enforced change of routine can change preference too, for instance, subjects asked to eat a low-fat diet report less liking for some high-fat foods (Mattes, 1993; Ledikwe et al., 2007), indicating that fat preference is at least partly affected by recent dietary experience.

Since learning and experience affect fat preference, it is hard to parse the inborn effects of genotype from these closely allied influences. There is cross cultural research using populations that differ in both genotype and culture and there have been some attempts to measure fat preference in different groups. One such study was focused on the fat preference of Pima Indians and Caucasians. Pima Indians are a native population in the United States with a high prevalence of obesity. They traditionally lived in a frugal desert climate and were of normal weight but as circumstances changed they have adopted a diet higher in calories and fat, and have become one of the most obese populations in the world. Although obesity is often associated with elevated fat preferences (Drewnowski et al., 1985), on average, the Pima Indians have lower preferences than do Caucasians (Salbe et al., 2004). Although genetics and environment probably both contribute to this group difference, the design of the experiment does not allow us to estimate the contribution of each factor.

16.7. GENETIC COMPONENT TO HUMAN FAT PREFERENCE

To try to untangle the effects of environment, learning, and culture, the study of twins provides a useful methodology. Monozygotic (MZ) twins are genetically identical (although recent studies challenge this notion (Fraga et al., 2005); see below) whereas dizygotic (DZ) twins are no more alike genetically than siblings. Thus, the behavior of MZ and DZ twins can be compared and heritability assessed. An alternative to twin studies are family studies, which follow a similar principle. The degree of genetic sharing between family members is compared with the degree of phenotypic similarity and the contribution of genotype to the trait is evaluated. The scientific literature about twins and fat preference was reviewed several years ago and the heritability estimates ranged widely from study to study (Reed et al., 1997). This conclusion has not changed when data from more recent studies are considered (Stafleu et al., 1994; Feunekes et al., 1997; Yeo et al., 1997; Vachon et al., 1998).

16.8. A NEW LOOK AT TWIN STUDIES OF HERITABILITY

As mentioned above, although twins are thought to be genetically identical, several lines of evidence suggest that this is not strictly accurate: the mutation rate for DNA replication, while low, is not zero, and so for a given cell lineage (including the germ cells), twins can differ in genotype based on spontaneous mutation. In addition, the results of recent studies suggest two other sources of differences in the genomes of twins. First, one of the surprises about the human genome is the extent to which small patches of the genome are duplicated, giving rise to multiple copies of genes (Sharp et al., 2005; Wong et al., 2007). While this type of duplication was known and appreciated as a part of a sequence of events (duplication and diversification), giving birth to new genes, the degree of duplication, especially among sensory genes, was unexpected (Nozawa et al., 2007). Even more surprising is that studies of MZ twins have revealed instances where genetically “identical” twins differ in gene copy number (Bruder et al., 2008). Second, the other source of differences in the genome of MZ twins is the degree of epigenetic modification, as measured by the methylation of particular parts of the genome. This methylation is thought to affect gene expression, and so twins that differ in methylation status at a particular location will presumably differ in the rate of transcription of a given gene (Fraga et al., 2005).

These observations about the genome of human twins have implications for fat preference. First, MZ twins that differ in body weight have been described and a key difference between these twins who are discordant for body weight is their preference for dietary fat (Rissanen et al., 2002), which raises the possibility that mutation, copy number variation, or epigenetic events might have a detectable effect on fat preference. The second implication is more general, which is that heritability estimates depend upon the assumption that MZ twins are genetically identical—if they are not, current estimates of heritability for the fat preference phenotype (as well as other traits) are underestimates.

16.9. FAMILY SIMILARITY AND HERITABILITY OF FAT PREFERENCE

Family and twin studies suggest fat intake and preference are heritable traits but individual studies differ in the strength of this effect. Table 16.1 contains a summary of the relevant statistics from studies that measured the percent of calories ingested as fat, which we will refer to as fat preference for simplicity. Some studies compute the percentage of the phenotype that can be accounted for by the additive effect of genes (heritability, h2) and some studies report the correlation among relative pairs, e.g., similarity among siblings. No attempt was made in these family correlation studies to estimate the additive effect of genes relative to household or unshared environmental effects. When these data are considered as a whole, the most obvious point is that the values range from no heritability at all to strikingly high values for a behavioral trait (>h2 = 0.48). Likewise, family similarity ranged from none (r = 0.0) to strong (r > 0.6). Other points also emerge from these studies. There was one study of twins reared apart, an experimental genetic design often considered the most informative (since twins are not reared in the same environment and the degree of similarity is thought to be genetic in origin). For this study, the heritability (h2) of fat intake was 0.35. This study makes the useful point that living in the same household is not a necessary prerequisite for family members to resemble each other in fat intake (Hur et al., 1998).

TABLE 16.1

TABLE 16.1

Family Correlations or Heritability Estimates of Percent of Calories as Fat

Examining the pattern of family correlations for fat intake revealed several other results. First, the method of data collection affected the strength of the family correlations. Values from food diary methods were generally higher (mean = 0.33, range = −0.23 to 0.69) than from food frequency questionnaires (mean = 0.16, range = −0.02 to 0.42). Age-related effects were also apparent because family correlations among people of the same generation, e.g., siblings, were higher (mean = 0.40, range = 0.04–0.69) than for people of different generations, e.g., parent–offspring (mean = 0.24, range = −0.23 to 0.49). Sex effects were not apparent. Family correlations computed for a same-sex pairing, e.g., mothers and daughters, were similar to those computed for opposite sex pairings, e.g., mothers and sons (meansame-sex = 0.38, range = −0.02 to 0.69 versus meanopposite-sex = 0.36, range = 0.12–0.54). The twin studies typically reported heritability (rather than family correlations) but the same trend as for the family correlations was observed: the food diary method associated with higher heritability (h2 = 0.48) than other methods of measuring fat intake (h2 = 0.0–0.42). In the twin studies, generation effects do not apply because all twins are of the same generation and sex effects could not be evaluated (because the studies did not typically report heritability separately for opposite sex DZ twin pairs). Overall the highest family correlations or heritability estimates of fat intake were obtained using food diaries from people of the same generation.

16.10. HERITABILITY OF PREFERENCE FOR SPECIFIC FOODS OR TYPES OF FOOD

When studying genetics of fat preference, sometimes investigators choose to focus on the intake of individual high-fat foods, e.g., cheese or ice cream rather than the total amount of fat consumed or the percent of calories from fat. A recent study of food preferences of twins reports a high heritability for foods in the category of meat and fish (Breen et al., 2006) and another found similarly high heritability for specific foods like hamburgers (Falciglia and Norton, 1994). Other investigators have used factor analysis to group foods into categories, finding that additive genetic effects accounted for about 44% of the variance in the intake of “high-fat” foods (Keskitalo et al., 2008a), or have asked questions about liking and food use frequency for sweet high-fat foods (e.g., ice cream) and salty high-fat foods (French fries), finding that depending on the twins samples, heritability estimates ranged from 0% to 71% (Keskitalo et al., 2008a,b). There is a heritable component to high-fat food consumption, but like the analysis of total fat intake, the degree of genetic contribution varies widely based on the population studied and how the phenotype is measured.

16.11. ASSOCIATION AND LINKAGE STUDIES OF FAT PREFERENCE

Twin and family studies are a classic method to study human heritability for a given trait but the genetic contribution to fat preference can be studied with other types of experimental designs. In the case of the studies above, the focus is on trying to assess the relative contribution of genes and environment whereas with the genetic methods described below, the focus is on identifying which genes might be particularly influential. To identify these genes, there are several types of approaches, the most common of which is an association study. In this type of design, biologically unrelated subjects are grouped by genotype and their intake or preference for dietary fat is compared. There are two types of association studies, a “candidate gene” approach in which only genes selected for some prior association with the trait are genotyped, or a “genome-wide association” approach in which alleles are densely genotyped throughout the genome. Both types of studies are called “association studies” because the association between genotype and phenotype is evaluated, but the designs differ in the scope of the genes considered.

In contrast to association studies which involve unrelated individuals, linkage studies incorporate people who are biologically related. In this type of experimental design, the degree of genetic sharing between relatives as well as their similarity or lack of similarly in fat preference and intake is calculated and compared. Linkage methods do not precisely localize the effect to a particular gene but rather identify a large chunk of DNA (that would contain many genes) which is shared by family members who are similar in phenotype. In the next section, the relationship of specific genotypes to fat intake in humans will be reviewed from both candidate gene association and linkage studies. As of now, no genome-wide association (GWA) studies of fat preference have been completed although their potential utility is discussed at the end of this chapter.

Candidate gene association studies focus on alleles from only one or a few genes and their association with fat intake or preference. An example of this type was a study of variation in the agouti-related protein (AgRP) gene and fat intake. The motivation to examine this particular gene comes from the study of obese mice. In the early days of mouse genetics, obese yellow mice were discovered (Danforth, 1927). The obesity was later determined to be due to the inappropriate expression of a gene involved in coat color (agouti) (Bultman et al., 1992). Investigators reasoned that the coat color gene was not likely to be normally involved in obesity but that it could be related to a different gene that did have a natural role in obesity. The discovery of agouti “related” protein confirmed this hypothesis (Shutter et al., 1997). This second gene is expressed in brain regions that regulate feeding and obesity and has several alleles in the human population, one of which is more common in Caucasians and one of which is more common in African-Americans. Each of these “most-common” alleles is associated with reduced fat intake (as a percent of total calories) in their respective racial population (Loos et al., 2005).

A potential target for candidate gene studies is CD36 because of its role in the sensory transduction of fatty acid perception (see above). If the CD36 gene is involved in fat sensing in humans as it is in mice, these differences could partially account for differences among people in oral fat perception. The human homologue of the mouse CD36 gene is located in the middle of human chromosome 7, and during the last several years, many alleles of CD36 have been discovered (Ma et al., 2004) (see Table 16.2). The CD36 gene and its alleles in humans have been studied by investigators who noticed its relationship with diet-induced disease such as diabetes. One hypothesis to explain these associations is that CD36 alleles might change fat perception and intake and thereby contribute to metabolic diseases. The discovery of a putative CD36 pseudogene allele (Table 16.2), which is analogous to a natural human “gene-knockout,” suggests that if this gene indeed codes for an oral fat receptor, there might be large differences among people with working and nonworking copies of the gene.

TABLE 16.2

TABLE 16.2

Alleles of CD36 in Humans and Known Health Relationships

There are two linkage studies that have examined fat intake as a phenotype, and both studies used food frequency questionnaires to assess the amount of fat habitually consumed by the subject (Cai et al., 2004; Collaku et al., 2004). One study reported linkage to fat intake on chromosome 2, a region which was also associated with body fatness. The other study used Caucasian and African-American families recruited at five locations in the United States. The results from this study were different: the main linkage finding for fat intake (irrespective of total calories) was on chromosome 12. These two studies were similar in design and methodology but the regions of the genome implicated were different and it is worth noting that neither of these regions overlapped genetic regions associated with fat preference in the mouse (Smith Richards et al., 2002). The individual results may be valid and the difference may be due to the genetic background of the populations studied, or the disparate results may be due to the relatively low heritability or low power (which led to noise and false positive results in one or both studies).

16.12. GENOME-WIDE ASSOCIATION AND FAT PREFERENCE

Candidate gene association studies such as the one described above are undertaken because there is evidence that a particular gene may be involved in a particular biological pathway associated with a genetic trait, but these types of studies have limitations. The results are often difficult to replicate and they do not assess every gene in the genome. However, there has been a recent change in the direction of human genetics of complex traits, with the introduction of GWA studies, which use a dense or ultradense mapping panel (so that nearly every gene can be included in the analysis). Most genes are tested for their association with the trait and therefore the design gives investigators the ability to discover new effects of genes that were not previously understood. This approach is done at a more fine-grained resolution than a linkage study, which then requires substantial followup to find a particular gene (within the broadly linked region). Given the advantages of GWA studies, progress in the study of other complex genetic traits has been swift. For instance, GWA studies suggest that alleles of the fat mass and obesity-associated (FTO) gene are related to obesity (Frayling et al., 2007), a finding that is replicable across many human populations (Frayling et al., 2007; Scott et al., 2007; Scuteri et al., 2007; Andreasen et al., 2008; Chang et al., 2008; Do et al., 2008; Freathy et al., 2008; Liu et al., 2008a,b; Marvelle et al., 2008; Ng et al., 2008; Qi et al., 2008; Tan et al., 2008). GWA studies have started to encompass traits similar to fat preference, like sweet taste-related traits (Hansen et al., submitted) and studies of fat intake and fat preference may be just around the corner.

16.13. SUMMARY AND CONCLUSIONS

Human food intake is subject to all manner of vicissitudes and this is equally true for particular aspects, like fat preference. Although fat preference has normally been studied from a metabolic or neuroscience perspective, the recent understanding that fat may be a taste quality in the same way as sweet or bitter has led to renewed interested in how and why fat is liked and consumed. Several lines of evidence point to genetic influences on fat preference. In mice and rats, inbred strains differ markedly in preference and since their environment is precisely controlled, these influences are ascribed mostly to genotype and certain regions have already been identified as harboring fat preference genes. Genetic studies in humans also suggest a strong streak of genetic influence but the manner in which fat preference is measured (food diaries versus food frequency questionnaires) influences the outcome of twin and family studies. Several investigators have begun the long march to discover genes that influence fat preference. Although the initial studies are few and inconsistent, new GWA methods providing greater stability are on the horizon. If these methods can be used to study fat preference in thousands (or tens of thousands) of individuals, progress might be quick in understanding the contribution of genotype to the preference for a high-fat diet.

Electronic Resources

dbSNP

http://www.ncbi.nlm.nih.gov/projects/SNP/

ACKNOWLEDGMENTS

The author’s research was supported by a National Institute of Diabetes and Digestive and Kidney Diseases Grant DK58797. Michael G. Tordoff and Brian Gantick commented on this work prior to publication. Discussions with Carol Christensen, Julie A Mennella, and Marcia Levin Pelchat enhanced the quality of this work.

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