Project 3: Effects of Androgen and Diet on Adipose Function

项目总结（见说明书）：常与多囊卵巢综合征相关的高雄激素血症和典型的高脂肪/高热量西式饮食（WSD）均可导致肥胖和代谢及生殖功能障碍。目前尚不清楚这些影响是否是独立的肥胖，或者如果高雄激素血症和WSD一起发挥代谢控制和生殖能力的协同作用。这是一个关键的问题，年轻的青春期前/围青春期女孩谁是受高雄激素血症的背景下，WSD。脂肪组织是高雄激素血症和WSD的单独和组合作用的整合位点的主要候选者;它对雄激素和WSD两者都有反应，并且能够产生脂肪细胞因子，所述脂肪细胞因子能够（a）在脂肪组织自身中产生炎症反应的反馈增强，以及（B）通过经典的内分泌和神经内分泌机制影响其他器官，包括生殖系统。本项目将在一项对青春期前雌性非人类灵长类动物的独特纵向研究中，单独或联合检查仔细控制睾酮暴露和WSD的后果。该研究还将包括一个去除睾酮和WSD的组，以确定雄激素效应的持续性，这将为减轻高雄激素血症和高脂肪/高热量饮食后果的治疗方法的设计提供信息。我们假设高雄激素血症和WSD诱导协同作用，对女性脂肪组织功能的功能障碍的影响，表现为改变细胞形态，胰岛素反应性，炎症状态和脂肪细胞因子分泌。为了解决这一假设，我们提出了以下具体目标：1。利用我们最近开发的脂肪外植体离体分析方法，确定高雄激素血症和WSD对脂肪细胞组织形态、分化状态和胰岛素作用的影响。2.确定高雄激素血症和WSD对脂肪炎症、纤维化、血管化和脂肪细胞因子分泌的影响。3.确定高雄激素血症对脂肪组织功能影响的可逆性。

PROJECT SUMMARY (See instructions): The hyperandrogenemia that often occurs in association with polycystic ovary syndrome and the typical high-fat/high-calorie Western-style diet (WSD) can both result in obesity and metabolic and reproductive dysfunction. It is unclear whether these effects are independent of obesity, or if hyperandrogenemia and WSD together exert synergistic effects on metabolic control and reproductive competence. This is a critical issue for young pre/peripubertal girls who are subject to hyperandrogenemia in the context of a WSD. Adipose tissue is a prime candidate for a site of integration of the separate and combined effects of hyperandrogenemia and WSD; it is responsive to both androgens and WSD, and capable of elaborating adipocytokines that can (a) produce a feedback enhancement of inflammatory responses in adipose tissue itself, as well as (b) influencing other organs, including the reproductive system, though classical endocrine and neuroendocrine mechanisms. This project will examine the consequences of carefully controlled testosterone exposure and WSD, singly and in combination, in a unique longitudinal study of prepubertal female nonhuman primates. The study will also include an arm in which testosterone and WSD are removed in order to ascertain the persistence of androgen effects, which will inform the design of therapeutic approaches to attenuate the consequences of hyperandrogenemia and high-fat/high-caloric diet. We hypothesize that hyperandrogenemia and WSD induce synergistic, dysfunctional effects on female adipose tissue function that are manifested as altered cellular morphology, insulin responsiveness, inflammatory status, and adipocytokine secretion. To address this hypothesis, we propose the following specific aims: 1. To determine the effects of hyperandrogenemia and WSD on adipocyte tissue morphology, differentiation state, and insulin action by exploiting our recently developed approaches for ex vivo analysis of adipose explants. 2. To determine the effects of hyperandrogenemia and WSD on adipose inflammation, fibrosis, vascularization, and adipocytokine secretion. 3. To determine the reversibility of the effects of hyperandogenemia on adipose tissue function.