Project 3: Effects of Androgen and Diet on Adipose Function

项目摘要(见说明)：经常与多囊卵巢综合征和典型的高脂肪/高热量西式饮食(WSD)相关的高雄激素血症可导致肥胖以及代谢和生殖功能障碍。目前尚不清楚这些影响是否独立于肥胖，或者高雄激素血症和WSD是否在代谢控制和生殖能力方面起到协同作用。这对于青春期前/青春期前的年轻女孩来说是一个关键问题，她们在WSD的背景下容易患上高雄激素血症。脂肪组织是高雄激素血症和WSD单独和综合作用的最佳候选者；它对雄激素和WSD都有反应，并能够产生脂肪细胞因子，这些脂肪细胞因子可以(A)在脂肪组织本身产生反馈性增强的炎症反应，以及(B)通过经典的内分泌和神经内分泌机制影响包括生殖系统在内的其他器官。该项目将在一项对青春期前女性非人类灵长类动物的独特纵向研究中，单独和联合检查仔细控制的睾酮暴露和WSD的后果。这项研究还将包括去除睾丸激素和WSD的手臂，以确定雄激素影响的持久性，这将为设计减轻高雄激素血症和高脂肪/高热量饮食后果的治疗方法提供信息。我们假设高雄激素血症和WSD对女性脂肪组织功能的协同作用和功能障碍表现为细胞形态、胰岛素反应性、炎症状态和脂肪细胞因子分泌的改变。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体外分析方法，确定高雄激素血症和WSD对脂肪组织形态、分化状态和胰岛素作用的影响。2.探讨高雄激素血症和WSD对大鼠脂肪炎症、纤维化、血管形成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.