Obesity is a major health concern in our society. In adulthood, obesity is a risk factor in many disorders including heart disease, stroke and hypertension. It also contributes to the incidence of Type II diabetes mellitus and exacerbates respiratory disease. Problems with weight control, however, often begin in childhood. Although most of the deleterious effects of excess weight gain do not become apparent until adulthood, obesity in childhood can have severe adverse effects on the child's health. In many families, problems with weight control appear to be inherited. Twin studies suggest that the heritability of obesity is greater than traits such as schizophrenia, alcoholism and atherosclerosis. Understanding the molecular mechanisms of weight homeostasis may lead to better methods of weight control, thus decreasing the prevalence of a major risk factor contributing to poor health. Seven gene loci are known that have effects on weight homeostasis in rodents. One of those loci, agouti, was recently cloned and shown to encode a small peptide. Normally agouti is expressed in the hair follicle and acts as a paracrine factor in the regulation of melanin synthesis by melanocytes. Dominant agouti mutants in the mouse also become obese, presumably though constitutive ectopic expression of the peptide. It was recently demonstrated that agouti is a competitive antagonist of the MSH receptor on melanocytes, thus explaining the ability of agouti to block the induction of eumelanin synthesis by alphaMSH. Agouti was also found to be a potent antagonist of another member of the melanocortin receptor family, the MC4 receptor. We propose to test the hypothesis that agouti causes obesity when expressed ectopically by antagonism of the normal function of one or more of the melanocortin receptors. Specifically, we propose to further characterize the distribution of melanocortin receptors in adipocytes and investigate their role in lipid metabolism. Using specific melanocortin receptor agonists and antagonists, pharmacologic studies will be designed to look at both peripheral and neural melanocortin receptor regulation of weight homeostasis. Finally, agouti action is quite complex and requires other gene loci for expression. Proteins interacting with agouti will be characterized and their role in agouti function elucidated. An investigation of the agouti peptide and its interactions with the melanocortin receptors in producing obesity will provide insight into one of the many mechanisms of normal weight control. These advancements may ultimately be used to devise methods or pharmacological agents for the regulation of weight homeostasis in man.
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