Adipose Tissue Glucocorticoid Metabolism and Weight Loss

描述（由申请人提供）：根据NIDDK支持影响公众健康的最严重疾病研究的使命，拟议的NRSA项目旨在了解与糖尿病、高血压和心血管疾病的发展密切相关的中心性肥胖的调节机制。与中枢性肥胖（即库欣病）的经典病理生理模型不同，肥胖状态不以血清皮质醇水平升高为特征。然而，人体对脂肪11 β -羟基类固醇脱氢酶1型（11¿-HSD1）的研究表明，与瘦受试者相比，肥胖受试者的mRNA表达和体外活性增加。这种酶在局部将非活性激素可的松转化为活性激素皮质醇。这些发现表明肥胖与脂肪细胞糖皮质激素代谢增加有关，但这是肥胖的原因还是后果尚不清楚。为了解决这个问题，我们提出的研究的总体目标是确定体重减轻5%对绝经后妇女脂肪糖皮质激素代谢的影响。由于11（3-HSD1）复杂的组织特异性调控，我们将1)使用一种新的微透析技术来测定体内糖皮质激素代谢；2)表征脂肪细胞中11¿-HSD1的表达，以及糖皮质激素作用的其他关键调节因子，包括己糖-6-磷酸脱氢酶（H6PDH）和糖皮质激素受体α (GRa)；3)比较具有不同代谢特征的皮下脂肪和股脂肪的体内活性和体外mRNA表达。我们假设腹部脂肪11¿-HSD1活性在体重减轻、能量平衡的状态下会增加，这表明组织特异性糖皮质激素代谢在肥胖的发展中起着因果作用。这些发现表明，11- 3HSD1抑制剂可能是维持体重和预防减肥后体重反弹的重要药物疗法。

DESCRIPTION (provided by applicant): In accordance with the mission of the NIDDK to support research on the most serious diseases affecting public health, the proposed NRSA project is aimed at understanding mechanisms regulating central obesity, which is strongly linked to the development of diabetes, hypertension, and cardiovascular disease. Unlike the classic pathophysiologic model of central obesity (i.e., Cushing's disease), the obese state is not characterized by elevated serum cortisol levels. However, human studies of adipose 11 beta-hydroxysteroid dehydrogenase type 1 (11¿-HSD1), the enzyme that locally converts the inactive hormone, cortisone, to the active hormone, cortisol, have demonstrated increased mRNA expression and in vitro activity in obese compared with lean subjects. These findings suggest that obesity is associated with increased adipocyte glucocorticoid metabolism, but it remains unclear whether this is a cause or consequence of obesity. To begin addressing this question, the global aim of our proposed studies is to determine the effects of a 5% weight loss on adipose glucocorticoid metabolism in postmenopausal women. Due to the complex, tissue-specific regulation of 11(3-HSD1, we will 1) use a novel microdialysis technique to determine in vivo glucocorticoid metabolism; 2) characterize adipocyte expression of not only 11¿-HSD1 but also other key regulators of glucocorticoid action including hexose-6-phosphate dehydrogenase (H6PDH) and glucocorticoid receptor alpha (GRa); and 3) compare in vivo activity and in vitro mRNA expression in subcutaneous abdominal and femoral fat, two accessible depots with different metabolic characteristics. We hypothesize that abdominal adipose 11¿-HSD1 activity will be increased in the weight-reduced, energy balanced state, which would suggest that tissue-specific glucocorticoid metabolism plays a causal role in the development of obesity. Such findings would imply that 11-(3HSD1 inhibitors may be an important pharmacotherapy for weight maintenance and the prevention of weight regain following weight loss. PUBLIC HEALTH RELEVANCE: The purpose of this research project is to study the effects of weight loss on the metabolism of the stress hormone cortisol in healthy, postmenopausal women. Our goal is to identify possible explanations for the accumulation of fat in the abdominal region.