Sex and the endocrine regulation of fuel metabolism

性别与燃料代谢的内分泌调节

• 批准号: 7036955
• 负责人: TRACY J HORTON
• 金额: $ 31.02万
• 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/7036955
• 关键词: alpha adrenergic receptor; beta adrenergic receptor; bioenergetics; blood chemistry; calorimetry; clinical research; endocrine pharmacology; epinephrine; gender difference; glucose metabolism; glycerol; gonadotropin releasing factor; hormone regulation /control mechanism; human subject; lipolysis; longitudinal human study; metabolomics; oxidation; palmitates; radiotracer; respiratory gas transport; testosterone; alpha adrenergic receptor; beta adrenergic receptor; bioenergetics; blood chemistry; calorimetry; clinical research; endocrine pharmacology; epinephrine; gender difference; glucose metabolism; glycerol; gonadotropin releasing factor; hormone regulation /control mechanism; human subject; lipolysis; longitudinal human study; metabolomics; oxidation; palmitates; radiotracer; respiratory gas transport; testosterone

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，在调节能量屈服底物的储存和代谢时，已经确定了男性和女性之间的许多重要差异。这种差异对性别特异性的病因和疾病治疗具有影响，尤其是具有强大代谢基础的疾病，例如肥胖，2型糖尿病和冠心病。 PI的初步数据表明，在女性与男性中，儿茶酚胺对运动的反应降低，这与循环甘油和自由脂肪酸（FFA）水平相似或更大的增加有关，但葡萄糖水平相似。此外，与男性相比，女性对运动过程中脂质对总燃料氧化的相对贡献更高。这表明对儿茶酚胺在女性与男性中的脂解作用的敏感性提高，并且在动员脂质时，使用脂质的倾向增加了。在匹配，休息，肾上腺素，去甲肾上腺素或男女合并的2个组合过程中证实了这些数据。也就是说，在每种输注过程中，女性对男性的甘油水平较高，而脂质对总燃料氧化的贡献更大。此外，在肾上腺素后，女性与男性的葡萄糖浓度明显更高，但在去甲肾上腺素或肾上腺素加上去甲肾上腺素后的葡萄糖浓度明显更高。当前建议的特定目的1中的研究将确定与系统底物变化和燃料氧化中这些性别差异有关的特定肾上腺素能受体（B和/或A）。这将通过对特定肾上腺素能激动剂和/或拮抗剂的休息输注以及稳定的同位素测量的甘油，棕榈酸酯和葡萄糖更换以及呼吸气交换和棕榈酸盐氧化的全身测量的结合来实现。为了开始确定性类固醇在儿茶酚胺刺激的底物代谢中的作用，具体的目标2将使用促性腺激素释放激素（GNRH）拮抗剂来抑制男性的内源性类动物生产。肾上腺素刺激的底物代谢将在被抑制的状态下进行前GNRH治疗，然后在睾丸激素后添加后添加。在这项GNRH抑制研究中，将通过甘油，FFA和葡萄糖更换以及全身呼吸道气体交换措施的稳定同位素测量来评估代谢。