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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK049692-04S1
Application #
2862817
Study Section
Metabolism Study Section (MET)
Program Officer
Mckeon, Catherine T
Project Start
1996-08-01
Project End
2000-03-31
Budget Start
1998-08-01
Budget End
2000-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Celi, F S; Canettieri, G; Yarnall, D P et al. (1998) Genomic characterization of the coding region of the human type II 5'-deiodinase gene. Mol Cell Endocrinol 141:49-52
Mitchell, B D; Blangero, J; Comuzzie, A G et al. (1998) A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. J Clin Invest 101:584-7
Silver, K; Mitchell, B D; Walston, J et al. (1997) TRP64ARG beta 3-adrenergic receptor and obesity in Mexican Americans. Hum Genet 101:306-11