DESCRIPTION (adapted from the application) Central (visceral) obesity contributes to an excess risk of diabetes, dyslipidemia, hypertension, and premature death from coronary heart disease. A feed-back loop model of weight regulation has emerged from recent studies of animals and humans: afferent hormones signal amount of fat mass to the central nervous system; weight regulation centers in the hypothalamus interpret these signals and control efferent systems including appetite, energy expenditure, and enzymes in the fat cell, such as lipoprotein lipase, that facilitate partitioning of energy into lipid storage. It is proposed in this grant that the hypothalamic-pituitary-adrenal axis is an effector system of hypothalamic weight regulatory centers and that increased cortisol production rates in the obese state directly regulate enzyme transcription in the fat cell to promote lipid uptake and central fat distribution. Cross sectional data from lean and obese humans using stable isotope enrichment determined by mass spectroscopy demonstrate that increases in cortisol production rates across the physiological range are associated with increased adipocyte lipoprotein lipase activity, accumulation of fat mass independent of non-fat mass, increased visceral fat, and increased insulin resistance. These findings, however, do not establish whether increased cortisol production causes, or is simply associated with these variables. To directly test whether cortisol enhances lipid uptake, fat mass accumulation, increased visceral fat mass, and insulin resistance, it is proposed to study the effect of administration of increasing doses of hydrocortisone (including doses within the physiological replacement range) in subjects with complete adrenal failure on these parameters. Finally, leading cellular candidates for the regulation of adipocyte lipoprotein lipase gene expression and fat cell differentiation, including PPAR-gamma and C/EBP, will be measured in adipose samples from the subjects in these studies to provide a mechanistic link between peripheral signaling systems such as cortisol and the adipocyte enzymes involved with fat partitioning. These studies will not only provide insight into the mechanisms of central obesity and its metabolic consequences, they also have great importance to clinicians who care for subjects with adrenal insufficiency as to the consequences of recommended replacement doses of cortisol on risk factors for heart disease.