Central (visceral) obesity is a strong risk factor for insulin resistance and noninsulin dependent diabetes mellitus (NIDDM), as well as for hypertension, dyslipidemia, and accelerated atherosclerosis (the so-called insulin resistance syndrome). The investigators identified the first mutation in the beta3AR, a seven membrane spanning G protein-linked receptor that is expressed in visceral adipose tissue. In four distinct cohorts (Pima Indians, Finnish Caucasians, Japanese, and French Caucasians), this mutation is associated with decreased resting metabolic rate, and several features of the insulin resistance syndrome including central obesity, hyperinsulinemia, and increased blood pressure, as well as the accelerated (earlier) onset of NIDDM. This missense mutation (codon 64TGGTrp CGGArg; W64R) predicts a nonconservative change in the first intracellular loop, a region that is important for proper function. Indeed the investigators preliminary data suggest a marked defect of W64R beta3AR in activating adenylyl cyclase. The investigators hypothesize that this mutation results in decreased receptor expression and/or defective signalling in visceral adipose tissue. Altered function may cause a decrease in beta3AR-stimulated lipolysis and energy expenditure (thermogenesis), which in turn leads to preferential deposition of visceral fat (central obesity), and thus increased susceptibility to insulin resistance and NIDDM.
The aims of this proposal are: 1) To determine the molecular mechanism(s) whereby this mutation increases genetic susceptibility to these disorders by expressing normal (wild type) and mutant W64R beta3AR in vitro, and studying receptor biosynthesis, intracellular trafficking, ligand binding, G protein association, and adenylyl cyclase activation; and 2) To define the importance of this mutation in Mexican Americans, a high risk minority population, by performing pedigree analysis in well-characterized subjects of the San Antonio Family Diabetes Study. These studies will (i) defie the molecular mechanism(s) whereby the W64R beta3AR mutation increases genetic susceptibility to obesity, insulin resistance and NIDDM; (ii) define the importance of this mutation in Mexican Americans; and (iii) provide important insights into the pathophysiology of these disorders as well as their treatment and prevention.
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