Sex and the endocrine regulation of fuel metabolism

描述（由申请人提供）：近年来，在能量产生底物的储存和代谢调节方面，已经确定了男性和女性之间的一些重要差异。这种差异对疾病的性别特异性病因学和治疗具有重要意义，特别是具有强烈代谢基础的疾病，如肥胖、2型糖尿病和冠心病。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有所降低，这与循环甘油和游离脂肪酸（FFA）水平的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，女性在运动过程中脂质对总燃料氧化的相对贡献更高。这表明女性对儿茶酚胺的溶脂作用比男性更敏感，当脂质被动员时，利用脂质的倾向增加。这一数据在配对、静息、注射肾上腺素、去甲肾上腺素或两者结合的男性和女性中得到证实。也就是说，在每次输注过程中，女性的甘油水平高于男性，脂质对总燃料氧化的贡献也更大。此外，服用肾上腺素后，女性的葡萄糖浓度明显高于男性，而服用去甲肾上腺素或肾上腺素加去甲肾上腺素后则没有。当前提案中Specific Aim 1的研究将确定在系统性底物变化和燃料氧化中涉及这些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、棕榈酸酯和葡萄糖代谢的稳定同位素测量，以及呼吸气体交换和棕榈酸酯氧化的全身测量来实现。为了开始确定性类固醇在儿茶酚胺刺激的底物代谢的性别差异中的作用，Specific Aim 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性类固醇的产生。将研究肾上腺素刺激的底物代谢在gnrh前的治疗，在抑制状态下，然后在睾酮添加回来。在这项GnRH抑制研究中，代谢将通过甘油、游离脂肪酸和葡萄糖代谢的稳定同位素测量和全身呼吸气体交换测量来评估。

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.