Genetic Appetite

Mutations can make you fat.

William Bateson, who coined the term genetics in 1906, would have been pleased with two recent articles that begin to provide a genetic explanation for obesity, a trait controlled by multiple genes and represented by a spectrum of body types. At a time when many believed that heritable traits "blended" inseparably, Bateson maintained that heritability was based on discrete "factors." One such factor, a nonfunctioning form of melanocortin 4 receptor (MC4R ), has been identified as the most important genetic determinant for severe early-onset obesity, a finding with implications for diagnosis, treatment, drug development, and public health.

Classical genetic traits occur in discrete forms (peas are either wrinkled or round), but adiposity varies continuously. This, plus the notion that dietary choices determine adiposity, has fueled skepticism that genes can cause obesity. But Stephen O�Rahilly and his team reported that almost 6% of 500 individuals with severe early-onset obesity had mutations that impair MC4R function, but none of 50 individuals from a non-obese control group did.¹

In Western society, advertising and concepts of self-image, to say nothing of the multibillion-dollar diet industry, feed the belief that slimness is a matter of free will. However, major discoveries in the last decade have demonstrated that some people are genetically predisposed to be obese. Like body temperature, adiposity is regulated by a homeostatic circuit: receptors in the hypothalamus sense the status of body stores, then initiate responses that maintain stability. In the brain, the MC4R is a key in this circuit, and it responds in opposite ways to two compounds released by neurons that regulate adiposity. In animal studies, alpha-melanocyte stimulating hormone (MSH) activates MC4R , causing reduced feeding and increased energy expenditure. Conversely, Agoutirelated protein (AGRP) inhibits MC4R , causing increased feeding and reduced energy expenditure.

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1  Farooqi, I.S. et al. (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New England Journal of Medicine 348:1085�95.