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

目前仅限核心实验室使用。 肥胖和非胰岛素依赖型糖尿病（NIDDM）是 异质性和重叠性疾病，两者都具有强烈的遗传 件.对皮马印第安人的研究表明， (RMR)是一种家族特征，能量消耗的减少 与肥胖风险增加有关，这反过来又导致 NIDDM。β-3-肾上腺素能受体（B3 AR）是一种七跨膜受体， 在脂肪细胞中表达的G蛋白连接受体， 参与脂解和静息代谢率的调节 （产热作用）。我们已经确定了B3 AR基因的第一个变体， （密码子64 TGGTrp->CGGArg; Trp 64 Arg）。这种错义突变预测了 受体第一个胞内环中的氨基酸变化， 可能对适当的细胞内运输很重要的区域， 与G蛋白偶联。Trp 64 Arg B3 AR基因变异已在 迄今为止的所有人群研究（高加索人，非洲裔美国人，日本人， 来自次大陆的中国人、萨摩亚人和印度人）， 南太平洋的瑙鲁人研究表明， Trp 64 Arg B3 AR与NIDDM早期发作的相关性或趋势， BMI和中心脂肪分布增加，高胰岛素血症和增加 舒张压 我们假设Trp 64 Arg B3 AR变异导致了 表达或异常信号传导特性导致降低 脂肪分解和能量消耗，这反过来又增加了对 肥胖和NIDDM。为了探索这一假设，我们将描述 非糖尿病非洲裔美国人受试者，他们要么是纯合子， 正常B3 AR、Trp 64 Arg B3 AR杂合子或纯合子，然后 在选择性腹腔内手术期间，获取网膜脂肪活检。之间 三种基因型，我们将比较B3 AR mRNA B-激动剂刺激 脂肪分解通过比较B3 AR基因型，这些研究将 1)定义Trp 64 Arg B3 AR突变的功能后果，2） 确定其在肥胖和NIDDM发展中的作用，以及3）提供 更好地了解B3 AR的生理功能。

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.