REGULATION OF ADIPOSE TISSUE REMODELING AND ENERGY HOMEOSTASIS

靶向脂肪组织功能以降低肥胖和改善胰岛素敏感性可以治疗肥胖症和糖尿病。核受体PPARGamma是脂肪组织发育和功能的关键调节因子，可被格列酮类糖尿病药物激活。PPARGamma能够调节两种不同功能类型脂肪组织的发育，即棕色和白色脂肪，以及白色脂肪组织的褐化，这表明它可能被不同的部分激动剂激活，进而促进不同转录辅助因子的招募。我们之前为了了解脂肪组织脂肪生成对PPARGamma内源性激活的贡献，鉴定了PexRAP(Peroxisomal Reductase Activing PPARGamma)，这是一种合成乙醚类脂的过氧体膜蛋白，是PPARGamma的潜在部分激动剂。在这个项目中，我们将研究PexRAP在脂肪组织重塑中的作用。虽然PexRAP在WAT中大量存在，并且在白色脂肪形成过程中表达增加，但在成熟的棕色脂肪组织(BAT)中PexRAP的蛋白水平很低。在棕色脂肪形成过程中，PexRAP蛋白，而不是它的mRNA急剧减少。抑制自噬稳定了PexRAP蛋白水平，表明PexRAP是蝙蝠发育过程中降解的目标。PexRAP在小鼠体内的失活促进脂肪细胞的褐化，增加能量消耗，降低肥胖，而其在培养细胞中的过表达抑制了生热基因的表达。对PexRAP相互作用蛋白的鉴定表明，PexRAP在脂肪细胞中的功能远远超出了其作为过氧体脂质合成酶的作用。PexRAP也存在于细胞核中，在那里它与脂肪细胞基因表达的调节因子相互作用，包括中介复合体的一个组成部分。基于这些结果，我们假设核定位的PexRAP作为一个分子开关，通过抑制米色脂肪细胞的产热和促进白色脂肪细胞的脂肪储存来编程脂肪组织重塑。为了检验这一假设，我们提出了三个具体目标。在目标1中，我们将研究PexRAP降解在生热和能量动态平衡调节中的生理重要性。在目标2中，我们将评估PexRAP在脂肪细胞中的转录调控作用。第三个目标将确定PexRAP相关的中介成分在脂肪细胞基因表达、脂肪组织发育和代谢动态平衡中的作用。总之，这项工作将对脂肪组织重塑的分子机制提供重要的见解。了解PexRAP及其相关蛋白是如何控制脂肪细胞特性的，对于设计增加棕色和米色脂肪质量以治疗肥胖的策略至关重要。

Targeting adipose tissue function to decrease adiposity and improve insulin sensitivity could treat obesity and diabetes. The nuclear receptor PPARgamma is a critical regulator of adipose tissue development and function and is activated by the glitazone family of diabetes drugs. The ability of PPARgamma to regulate the development of two functionally distinct types of adipose tissue, brown and white fats, as well as browning of white adipose tissue (WAT), suggests that it may be activated by different partial agonists that in turn promote recruitment of distinct transcriptional cofactors. Our previous efforts to understand the contribution of adipose tissue lipogenesis to the endogenous activation of PPARgamma led to the identification of PexRAP (Peroxisomal Reductase Activating PPARgamma), a peroxisomal membrane protein that synthesizes ether lipids, potential partial agonists for PPARgamma. In this project, we will study the role of PexRAP in adipose tissue remodeling. Although PexRAP is abundantly present in WAT and its expression increases during white adipogenesis, the protein levels of PexRAP in mature brown adipose tissue (BAT) are low. The PexRAP protein, but not its mRNA, dramatically decreases during brown adipogenesis. Inhibition of autophagy stabilized PexRAP protein levels, suggesting that PexRAP is targeted for degradation during BAT development. PexRAP inactivation in mice promotes adipocyte browning, increased energy expenditure and decreased adiposity, while its overexpression in cultured cells inhibits thermogenic gene expression. Identification of PexRAP-interacting proteins suggests that the function of PexRAP in adipocytes extends well beyond its role as a peroxisomal lipid synthetic enzyme. PexRAP is also present in the nucleus, where it interacts with regulators of adipocyte gene expression, including a component of the Mediator complex. Based on these results, we hypothesize that nuclear localized PexRAP functions as a molecular switch that programs adipose tissue remodeling by repressing thermogenesis in beige adipocytes and promoting lipid storage in white adipocytes. To test this hypothesis, we propose three specific aims. In aim 1, we will study the physiological importance of PexRAP degradation in the regulation of thermogenesis and energy homeostasis. In aim 2, we will evaluate the transcriptional regulatory role of PexRAP in adipocytes. The third aim will identify the role of a PexRAP-associated Mediator component in adipocyte gene expression, adipose tissue development and metabolic homeostasis. Together, this work will provide a significant insight into molecular mechanisms involved in adipose tissue remodeling. Understanding how PexRAP and its associated proteins control adipocyte identity will be critical for designing strategies to increase brown and beige fat mass to treat obesity.