replicated across five studies. Probable reasons for nonreplication including population stratification (i.e., the combination of individuals from different racial/ethnic backgrounds), publication bias, Type 1 errors, and insufficient statistical power [126].

Third, among the phenotypes investigated that were not body composition measures, the vast majority were metabolic or physiological measures rather than measures of food intake, appetite, or food preferences. Thus, as described below, behavioral measures have been largely unrepresented in genotype studies and this may represent an opportunity for future research.

Fourth, single-gene mutations likely account for a small percent of the cases of human obesity in the general population. For most obese individuals, obesity likely results from the influence of multiple genes on different chromosomes that work additively and through gene-gene interactions [5]. Among the cases of monogenic obesity reported in the literature, most have been related to mutations in the melanocortin 4 receptor (MC4R) gene [125].

Finally, for most individuals in the population, the specific physiological mechanisms by which genes influence obesity probably involve both energy intake and expenditure pathways. A detailed discussion on this topic is beyond the scope of this report, which is more geared towards behavioral phenotypes, but is provided elsewhere [127-129]. Several genes have been implicated in the regulation of energy expenditure, including those related to mitochondrial uncoupling proteins (i.e., UCP1, UPC2, and UCP3 genes), the adrenergic systems (i.e., β2-AR and β3-AR genes), and the growth and development of the adipocyte (PPARγ gene) [125, 127]. Although these genes are involved in energy expenditure pathways, Loos and Bouchard [127] point out that most genetics studies examined these genes in relation to obesity-related phenotypes and not energy expenditure phenotypes per se.

The physiological pathways related to appetite are complicated and, as reviewed by Badman and Flier [130], involve the integration of short-term satiety signals from the gut to the brain along with longer-term homeostatic systems. Figure C-2 depicts an overview of these physiological pathways, which involve the integrated signaling of POMC, AGRP, MC4R, and NPY systems. As Loos and Bouchard note [127], there have been relatively inconsistent findings linking obesity phenotypes to genes for these proteins. Perhaps the most encouraging findings in the literature involve the MC4R gene, which, as discussed in the next section, has been associated with human food intake in a few preliminary studies.

Genetic Influences on Food Intake

A relatively small number of studies have tested genetic influences on eating phenotypes, independent from body fat. They provide data pertinent

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