Regulation of Cortisol Metabolism and Fat Patterning

描述（由申请人提供）：中心（内脏）肥胖导致男性和女性患糖尿病、血脂异常和冠心病死亡的风险过高。男性和女性的性腺功能减退通常会导致向心性肥胖，但引起脂肪分布变化的机制尚不清楚。这里提供的数据支持性类固醇激素调节下丘脑-垂体-肾上腺（HPA）轴在男性和女性内脏肥胖的表达中的作用。最近的研究还表明，在内脏肥胖和胰岛素抵抗的表达中，通过酶11 b-羟基类固醇脱氢酶1（HSD 1）在脂肪细胞中增强可的松向皮质醇的转化的作用。因此，本基金的第一个目的是通过定量尿糖皮质激素代谢物、细胞内皮质醇水平和脂肪细胞中糖皮质激素受体结合能力，前瞻性地确定性类固醇（女性雌激素，男性睾酮）是否调节HPA活性、全身游离皮质醇水平、脂肪活检和全身HSD 1活性。连续的随访研究访视将确定这些激素对这些结果的影响的时间过程。此外，基于有证据表明中心性（内脏）肥胖受试者的肌肉和脂肪中存在“异位”甘油三酯沉积，并且这些沉积可能在这些组织中的胰岛素抵抗中发挥病因学作用，将使用磁共振波谱（MRS）量化这些受试者的肌内（IMCL）和肝内脂肪（IHF），沿着通过CT扫描测量内脏脂肪。MRS技术的可用性为非侵入性研究可能导致异位脂肪沉积和胰岛素抵抗的机制提供了独特的机会。因此，该补助金的第二个目的是包括通过CT测量中央脂肪模式，通过MRS测量肌肉和肝脏中的异位脂肪沉积，以及测量接受性类固醇激素治疗的受试者的胰岛素敏感性。了解导致向心性肥胖和胰岛素抵抗的表达的生理学对于开发治疗这些疾病的新工具以及预防男性和女性的糖尿病和心血管风险将是重要的。

DESCRIPTION (provided by applicant): Central (visceral) obesity contributes to an excess risk of diabetes, dyslipidemia, and death from coronary heart disease in men and women. Hypogonadism in both men and women typically leads to central obesity but the mechanisms causing this change in fat distribution are poorly understood. Data presented here support a role for sex steroid regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the expression of visceral obesity in men and women. Recent studies also suggest a role for enhanced conversion of cortisone to cortisol in the adipocyte by the enzyme 11 b-hydroxysteroid dehydrogenase 1 (HSD 1) in the expression of visceral adiposity and insulin resistance. The first aim of this grant is, therefore, to prospectively determine if sex steroids (estrogen in women, testosterone in men) regulate HPA activity, systemic free-cortisol levels, HSD 1 activity in fat biopsies and in the whole body by quantifying urinary glucocorticoid metabolites, and intracellular cortisol levels and glucocorticoid receptor binding capacity in adipocytes. Sequential follow-up study visits will determine the time course of these hormonal effects on these outcomes. In addition, based on evidence indicating that subjects with central (visceral) obesity have "ectopic" triglyceride deposition in muscle and fat, and that these depositions may play an etiological role in insulin resistance in these tissues, magnetic resonance spectroscopy (MRS) will be used to quantify intramyocellular (IMCL) and intrahepatic fat (IHF), along with measures of visceral fat by CT scan, in these subjects. Availability of the MRS technique offers a unique opportunity to non-invasively study mechanisms that might result in ectopic fat deposition and insulin resistance. Therefore, the second aim of this grant is to include measurements of central fat patterning by CT, ectopic fat deposition in muscle and liver by MRS, and measurement of insulin sensitivity in the subjects undergoing sex steroid hormonal therapy. Understanding the physiology resulting in the expression of central obesity and insulin resistance will be important in developing new tools to treat these disorders and in the prevention of diabetes and cardiovascular risk in men and women.