Obesity and aging are associated with insulin resistance, glucose intolerance, hypertriglyceridemia and reduced high density lipoprotein (HDL) cholesterol levels in man. These metabolic abnormalities may be more severe in obese subjects with an upper body fat distribution (waist to hip circumference ratio greater than 0.97, WHR). This research evaluates the mechanism(s) for the abnormal glucose and lipoprotein metabolism in healthy, obese, sedentary men aged 45-75 years and determines the relationship of adipose mass and its distribution to metabolism. The population will be sedentary middle-aged (45-59 years) and old (60-75 years) obese men (greater than 20% body fat) with an upper body fat distribution (WHR greater than 0.97), men matched for percent body fat with a lower body fat distribution (WHR less than 0.87), and lean sedentary males of comparable age and WHR. Insulin secretion and sensitivity will be determined using the hyperglycemic clamp, lipoprotein lipid levels will be measured, and the HDL subclasses related to postheparin plasms lipoprotein lipase (LPL) and hepatic lipase activity. The response of lipoprotein lipids and HDL subclasses to hyperinsulinemia (250-300MuU/ml) during a euglycemic clamp will be related to glucose utilizataion, adipose tissue LPL activity, and the adrenergic regulation of lipolysis and lipogenesis in biopsies from gluteal and hypogastric fat depots. Weight loss improves lipid and glucose metabolism in obese individuals, but the mechanism of the effects of weight loss on these metabolic processes in subjects with an upper body vs. those with a lower body fat distribution has not been determined. Analysis of the results involves statistical comparisons of data at baseline, in the weight-reduced state and to lean controls. The biological effects of aging, that is """"""""primary"""""""" aging as distinct from """"""""secondary"""""""" effects like as obesity and fat distribution, will be determined using multiple regression analysis and analysis of variance. Understanding the mechanisms responsible for these metabolic abnormalities in obese aged men with an upper body fat distribution, and determining the metabolic effects of weight loss should provide insight in to therapies to reduce risk for coronary artery disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Clinical Investigator Award (CIA) (K08)
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Johns Hopkins University
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