ROLE OF LIPOLYSIS IN HUMAN OBESITY AND FASTING

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The second National Health and Nutrition Examination survey found that 26% of U.S. adults, or about 34 million people, aged 20-75 years were obese (greater than 120% ideal body weight). However, despite the high prevalence of obesity and the associated increased risk of such conditions as diabetes and hyperlipidemia, it is not known whether the health risks of obesity are simply a function of the excessive amount of adipose tissue or whether regulation of adipose tissue is also defective in obese persons. The presumed physiological role of fat is to provide an alternative fuel during periods of caloric deprivation. The factors responsible for acceleration of lipolysis during fasting are incompletely understood, but they are presumably a combination of hormonal, neural and metabolic influences. Preliminary information suggests that fasted obese persons are protected against excessive stimulation of lipolysis and overwhelming of the bodies capacity to consume free fatty acids, possibly form an alteration in the hormonal milieu. The proposed experiments will examine the regulation by insulin of lipolysis, FFA reesterification and fat oxidation in lean nd obese nondiabetic volunteers, to determine whether abnormalities of fat metabolism could explain the insulin resistance of carbohydrate metabolism. The next series of experiments will evaluate the factors that control lipolysis, and the relationship of lipolysis to glucose homeostasis and protein conservation, in overnight and three day fasted lean and obese nondiabetic volunteers. These experiments will monitor the effect of lipid, glucose and protein turnover of selective removal or blockade of hormonal, neural or metabolic factors know to influence lipid metabolism. The penultimate experiments will investigate whether enhancement of lipolysis during fasting is impaired in obese persons as a result of reduced hormonal stimulation and, if so, whether replacement of the hormonal deficiency, most likely growth hormone, can accelerate lipolysis without untoward metabolic consequences. If this is the case, the final experiment will evaluate the effect of chronic growth hormone treatment on fat, protein and carbohydrate metabolism in obese subjects consuming a hypocaloric diet.