CELL BIOLOGY OF TRP64ARG BETA-3-ADRENERGIC RECEPTOR IN OBESITY AND NIDDM

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Core Laboratory utilization only, at this time. Obesity and noninsulin dependent diabetes mellitus (NIDDM) are heterogeneous and overlapping disorders, both with strong genetic components. Studies in Pima indians have shown that resting metabolic rate (RMR) is a familial trait and that a reduction in energy expenditure is associated with an increased risk of obesity, which in turn leads to NIDDM. The Beta-3-Adrenergic receptor (B3AR) is a seven-membrane spanning G-protein-linked receptor that is expressed in adipose cells, and is involved in the regulation of lipolysis and resting metabolic rate (thermogenesis). We have identified the first variant in the B3AR gene (codon 64 TGGTrp->CGGArg; Trp64Arg). This missense mutation predicts an amino acid change in the first intracellular loop of the receptor, a region that may be important for proper intracellular trafficking and coupling to G-proteins. The Trp64Arg B3AR gene variant has been found in all populations studies to date (Caucasians, African-Americans, Japanese, Chinese, Samoans and Indians from the subcontinent) with the exception of the Nauruans of the South Pacific. Studies have demonstrated significant association or trends of the Trp64Arg B3AR with an earlier onset of NIDDM, increased BMI and central fat distribution, hyperinsulinemia and increased diastolic blood pressure. We hypothesize that the Trp64Arg B3AR variant results in decreased expression or abnormal signalling properties leading to decreased lipolysis and energy expenditure which in turn increases susceptibility to obesity and NIDDM. To explore this hypothesis, we will characterize nondiabetic African-American subjects who are either homozygous for the normal B3AR, heterozygous, or homozygous for the Trp64Arg B3AR and then during elective intraabdominal surgery, obtain omental fat biopsies. Among the three geneotypes, we will compare B3AR mRNA B-agonist stimulated lipolysis. By making comparisons among B3AR genotypes, these studies will 1) define the functional consequences of the Trp64Arg B3AR mutation, 2) define its role in the develpment of obesity and NIDDM, and 3) provide a greater understanding of the physiologic function of the B3AR.