Roles for Wnt Signaling in Adipose Tissue

 描述（由申请人提供）：肥胖是美国慢性疾病和过早死亡的主要原因。这项提案的目的是进一步了解肥胖如何发展以及肥胖如何导致代谢疾病。特别是，我们将研究我们在上一个资助周期中开发的一个领域-通过Wnt信号调节脂肪细胞线粒体生物发生和代谢。培养的脂肪细胞暴露于Wnt 3a激活信号通路并增加线粒体调节因子的表达，如过氧化物酶体增殖物激活受体-β-辅激活因子1α（Pgc 1 α）、线粒体转录因子A（Tfam）和核呼吸因子（Nrfs）。此外，Wnt 3a调节包括柠檬酸合酶在内的线粒体蛋白亚类的赖氨酸乙酰化，其活性 随着Wnt处理的增加。基于这些数据，我们提出的实验来测试的假设，即线粒体蛋白的翻译后修饰的调节介导的氧化代谢的Wnt 3a的影响，它是Wnt 11启动内源性Wnt信号在这种情况下。我们已经发现，抑制Wnt信号的分泌卷曲相关蛋白5（SFRP 5），这是诱导脂肪组织肥胖，需要脂肪细胞肥大，响应肥胖饮食，我们建议使用我们的新的动物模型，以扩大SFRP 5和Wnt信号在脂肪组织生物学中的作用。为了验证这些假设，我们提出了以下具体目标：1）研究SFRP 5在脂肪细胞中的表达调节脂肪细胞肥大和肥胖发展的机制，以及2）确定Wnt信号传导刺激线粒体生物发生和代谢的机制。这些研究将极大地推进我们对控制脂肪细胞代谢的机制的理解。重要的是，这项工作将为该领域解决Sfrp 5在脂肪组织和葡萄糖稳态/胰岛素敏感性中的调节和功能作用的相互矛盾的数据。我们的研究结果也将进一步促进我们的机制的理解Wnt信号如何通过乙酰化和活性的线粒体蛋白在脂肪细胞和肥胖症的氧化代谢。这些发现也可能揭示Wnt信号对肝脏和肌肉线粒体功能的类似调节过程。因此，从成功完成拟议的研究中获得的见解对于我们理解脂肪组织生理学以及肥胖和相关代谢并发症的发展至关重要。

 DESCRIPTION (provided by applicant): Obesity is the leading cause of chronic illness and premature death in the United States. The goal of this proposal is to further our understanding of how obesity develops and how obesity causes metabolic disease. In particular we will investigate an area that we developed during the last funding cycle - the regulation of adipocyte mitochondrial biogenesis and metabolism by Wnt signaling. Exposure of cultured adipocytes to Wnt3a activates signaling pathways and increases expression of mitochondrial regulators, such as peroxisome proliferator-activated receptor-ᵧ coactivator 1α (Pgc1α), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors (Nrfs). In addition, Wnt3a regulates lysine acetylation of a subset of mitochondrial proteins including citrate synthase, whose activity increases with Wnt treatment. Based on these data, we propose experiments to test the hypotheses that regulation of posttranslational modifications on mitochondrial proteins mediates effects of Wnt3a on oxidative metabolism, and that it is Wnt11 that initiates endogenous Wnt signaling in this context. We have found that inhibition of Wnt signaling by secreted frizzled-related protein 5 (SFRP5), which is induced in adipose tissue with obesity, is required for adipocytes to hypertrophy in response to an obesigenic diet, and we propose to use our novel animal models to extend the roles of SFRP5 and Wnt signaling in adipose tissue biology. To test these hypotheses we propose the following specific aims: 1) to investigate mechanisms by which expression of SFRP5 in adipocytes regulates adipocyte hypertrophy and the development of obesity, and 2) to determine mechanisms by which Wnt signaling stimulates mitochondria biogenesis and metabolism. These studies will greatly advance our understanding of the mechanisms that control adipocyte metabolism. Importantly this work will resolve for the field the conflicting data on the regulation and functional roles of Sfrp5 in adipose tissue and glucose homeostasis/insulin sensitivity. Our results will also further our mechanistic understanding of how Wnt signaling regulates oxidative metabolism through acetylation and activity of mitochondrial proteins in adipocytes and with obesity. These findings may also shed light on similar regulatory processes of Wnt signaling on mitochondrial function in liver and muscle. Thus, insights gained from the successful completion of proposed studies will be crucial for our understanding of adipose tissue physiology and the development of obesity and associated metabolic complications.