Obesity is characterized by increased body fat and propensity to numerous obesity-related illnesses, including hypertension, type II diabetes, cardiovascular, pulmonary and gallbladder disease, as well as some forms of cancer. The molecular basis of obesity in women is unknown A novel mutation (codon 64 TGG(TrP)->CGG(Arg); W64R) in the beta3- adrenergic receptor (beta3AR) gene was recently detected in a number of ethnic populations. This mutation predicts a minor amino acid change in the first intracellular loop of this seven membrane-spanning receptor. The beta-adrenergic receptor is thought to play an important role in the regulation of energy expenditure and lipolysis. Subjects who harbor the mutation, tend to have a lower resting metabolic rate, higher body mass index and earlier onset of type II diabetes. Little is known, however, regarding the possible metabolic role of the BAR mutation as a contributor to low levels of energy expenditure and fat oxidation that lead to obesity in older women. Our overall hypothesis is that the inherited mutation in the beta3AR gene contributes to the genetic basis of obesity via low levels of energy expenditure and reduced lipolysis and fat oxidation in older women. Moderately obese women (50-65yr) who are homozygous for the beta3AR mutation (MM) or heterozygous (NM) for the beta3AR mutation will be weight-reduced, metabolically stabilized and compared to never-obese homozygous normal controls (NN). We hypothesize that use of a post- obese model will unmask differences in energy expenditure and fat metabolism that would otherwise be obscured by the obese state. Total daily energy expenditure, resting metabolic rate, the thermic effect of a meal, free-living physical activity, rates of free fatty acid appearance and fat oxidation will be compared among genotypes after weight reduction. These studies will help define the metabolic consequences of the mutation in the beta3AR gene in the regulation of daily energy expenditure and fat metabolism in older women.
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