Sex and the endocrine regulation of fuel metabolism

性别与燃料代谢的内分泌调节

• 批准号: 7430394
• 负责人: TRACY J HORTON
• 金额: $ 28.45万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430394
• 关键词: Accounting; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Back; Body fat; Body measure procedure; Catecholamines; Coronary heart disease; Data; Diabetes Mellitus; Disease; Endocrine; Endocrine system; Energy Metabolism; Epinephrine; Etiology; Exercise; Glucose; Glycerol; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hormone Antagonists; Hormones; Incidence; Infusion procedures; Knowledge; Lipids; Lipolysis; Measures; Metabolic; Metabolic Diseases; Metabolism; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Norepinephrine; Numbers; Obesity; Palmitates; Peripheral; Play; Pre-study; Prevention; Production; Regulation; Relative (related person); Rest; Role; Sex Characteristics; Sympathetic Nervous System; Testosterone; United States; Woman; adrenergic; base; carbohydrate metabolism; disorder prevention; disorder risk; hormone regulation; insight; men; metabolic abnormality assessment; mortality; oxidation; respiratory gas; response; sex; stable isotope

DESCRIPTION (provided by applicant): In recent years, a number of important differences between men and women have been identified in the regulation of the storage and metabolism of energy yielding substrates. Such differences have implications for sex-specific etiology and treatment of diseases, especially diseases that have a strong metabolic basis such as obesity, type 2 diabetes, and coronary heart disease. The PI has preliminary data showing that there is a reduced catecholamine response to exercise in women vs men and that this is associated with similar or greater increases in circulating glycerol and free-fatty acid (FFA) levels, but similar glucose levels. In addition, women have a higher relative contribution of lipid to total fuel oxidation during exercise compared to men. This suggests an increased sensitivity to the lipolytic action of catecholamines in women vs men and an increased propensity to utilize lipid when lipid is mobilized. This data was confirmed during matched, resting, infusions of epinephrine, norepinephrine, or the 2 combined in men and women. That is, women had higher glycerol levels vs men and a greater contribution of lipid to total fuel oxidation during each infusion. In addition, glucose concentrations were significantly greater in women vs men after epinephrine but not after norepinephrine or epinephrine plus norepinephrine. Studies in Specific Aim 1 of the current proposal will identify the specific adrenergic receptors (B and/or a) involved in these sex differences in systemic substrate changes and fuel oxidation. This will be achieved via resting infusions of specific adrenergic agonists, and/or antagonists, combined with stable isotope measures of glycerol, palmitate and glucose turnover and whole-body measures of respiratory gas exchange and palmitate oxidation. In order to begin to determine the role of the sex-steroids in the sex differences in catecholamine stimulated substrate metabolism, Specific Aim 2 will use a gonadotropin-releasing hormone (GnRH) antagonist to suppress endogenous sex-steroid production in men. Epinephrine stimulated substrate metabolism will be studied pre-GnRH treatment, in the suppressed state and then following testosterone add back. In this GnRH suppression study, metabolism will be assessed via stable isotope measures of glycerol, FFA and glucose turnover and whole-body respiratory gas exchange measures.

描述(由申请人提供)：近年来，在调节产生能量的底物的储存和新陈代谢方面，已经确定了男性和女性之间的一些重要差异。这些差异对特定性别的病因学和疾病的治疗有影响，特别是肥胖症、2型糖尿病和冠心病等具有很强代谢基础的疾病。PI的初步数据显示，与男性相比，女性对运动的儿茶酚胺反应减弱，这与循环甘油和游离脂肪酸(FFA)水平相似或更高有关，但血糖水平相似。此外，与男性相比，女性在运动过程中脂肪在总燃料氧化中的相对贡献更高。这表明，与男性相比，女性对儿茶酚胺的脂解作用更加敏感，当脂质被动员时，利用脂肪的倾向增加。这一数据在男性和女性匹配的静息注射肾上腺素、去甲肾上腺素或两者联合使用时得到证实。也就是说，在每次输液过程中，女性的甘油水平高于男性，脂肪对总燃料氧化的贡献更大。此外，服用肾上腺素后，女性的血糖浓度显著高于男性，但在服用去甲肾上腺素或肾上腺素加去甲肾上腺素后，女性的血糖浓度并不明显。目前提案中特定目标1的研究将确定参与这些系统底物变化和燃料氧化的性别差异的特定肾上腺素能受体(B和/或a)。这将通过静息输注特定的肾上腺素能激动剂和/或拮抗剂，结合甘油、棕榈酸酯和葡萄糖周转的稳定同位素措施以及全身呼吸气体交换和棕榈酸酯氧化的措施来实现。为了开始确定性类固醇在儿茶酚胺刺激的底物代谢中的性别差异中的作用，特定目标2将使用促性腺激素释放激素(GnRH)拮抗剂来抑制男性内源性类固醇的产生。肾上腺素刺激的底物代谢将在GnRH治疗前研究，在抑制状态下，然后在睾酮补充回来。在这项抑制促性腺激素释放激素的研究中，代谢将通过甘油、游离脂肪酸和葡萄糖周转的稳定同位素测量以及全身呼吸气体交换测量来评估。