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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Page, Stephanie T; Krauss, Ronald M; Gross, Coleman et al. (2012) Impact of mifepristone, a glucocorticoid/progesterone antagonist, on HDL cholesterol, HDL particle concentration, and HDL function. J Clin Endocrinol Metab 97:1598-605
Klopfenstein, Bethany J; Purnell, Jonathan Q; Brandon, David D et al. (2011) Determination of cortisol production rates with contemporary liquid chromatography-mass spectrometry to measure cortisol-d(3) dilution after infusion of deuterated tracer. Clin Biochem 44:430-4
Kratz, Mario; Weigle, David S; Breen, Patricia A et al. (2010) Exchanging carbohydrate or protein for fat improves lipid-related cardiovascular risk profile in overweight men and women when consumed ad libitum. J Investig Med 58:711-9
Purnell, Jonathan Q; Kahn, Steven E; Samuels, Mary H et al. (2009) Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss. Am J Physiol Endocrinol Metab 296:E351-7
Uckun-Kitapci, Aysin; Haqq, Andrea M; Purnell, Jonathan Q et al. (2008) Serum ghrelin concentrations are increased in children with growth hormone insensitivity and decrease during long-term insulinlike growth factor-I treatment. J Investig Med 56:26-31
Purnell, J Q; Cummings, D; Weigle, D S (2007) Changes in 24-h area-under-the-curve ghrelin values following diet-induced weight loss are associated with loss of fat-free mass, but not with changes in fat mass, insulin levels or insulin sensitivity. Int J Obes (Lond) 31:385-9
Koren, Mikhail S; Purnell, Jonathan Q; Breen, Patricia A et al. (2007) Changes in plasma amino Acid levels do not predict satiety and weight loss on diets with modified macronutrient composition. Ann Nutr Metab 51:182-7
Purnell, Jonathan Q; Bland, Lisa B; Garzotto, Mark et al. (2006) Effects of transdermal estrogen on levels of lipids, lipase activity, and inflammatory markers in men with prostate cancer. J Lipid Res 47:349-55
Koren, Mikhail S; Purnell, Jonathan Q; Breen, Patricia A et al. (2006) Plasma C-reactive protein concentration is not affected by isocaloric dietary fat reduction. Nutrition 22:444-8
Weigle, David S; Breen, Patricia A; Matthys, Colleen C et al. (2005) A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations. Am J Clin Nutr 82:41-8

Showing the most recent 10 out of 21 publications