Sex and the endocrine regulation of fuel metabolism

描述（由申请人提供）：近年来，在调节能量产生底物的储存和代谢方面，已经确定了男性和女性之间的许多重要差异。这种差异对疾病的性别特异性病因学和治疗有影响，特别是具有强烈代谢基础的疾病，如肥胖症，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降低，这与循环甘油和游离脂肪酸（FFA）水平相似或更高的增加有关，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。这表明女性与男性相比对儿茶酚胺的脂解作用的敏感性增加，并且当脂质动员时利用脂质的倾向增加。该数据在男性和女性的肾上腺素、去甲肾上腺素或2种联合输注的匹配、静息、输注期间得到证实。也就是说，女性的甘油水平高于男性，并且在每次输注期间脂质对总燃料氧化的贡献更大。此外，女性在注射肾上腺素后血糖浓度显著高于男性，但在注射去甲肾上腺素或肾上腺素加去甲肾上腺素后血糖浓度则无显著差异。当前提案的特定目标1研究将确定参与全身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）。这将通过特定肾上腺素能激动剂和/或拮抗剂的静息输注，结合甘油、棕榈酸盐和葡萄糖周转的稳定同位素测量以及呼吸气体交换和棕榈酸盐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底物代谢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）拮抗剂抑制男性内源性性类固醇的产生。将在GnRH处理前、抑制状态下以及睾酮加回后研究肾上腺素刺激的底物代谢。在这项GnRH抑制研究中，将通过甘油、FFA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代谢。

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.