REGULATION OF ADIPOSE TISSUE REMODELING AND ENERGY HOMEOSTASIS

针对脂肪组织功能降低脂肪，改善胰岛素敏感性，可以治疗肥胖和糖尿病。核受体PPARgamma是脂肪组织发育和功能的关键调节因子，并被格列酮家族糖尿病药物激活。PPARgamma调节两种功能不同的脂肪组织（棕色脂肪和白色脂肪）的发育，以及白色脂肪组织的褐变（WAT）的能力表明，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募集。我们之前的努力了解脂肪组织脂肪生成对内源性PPARgamma激活的贡献，导致了PexRAP（过氧化物酶体还原酶激活PPARgamma）的鉴定，这是一种合成醚脂质的过氧化物酶体膜蛋白，可能是PPARgamma的部分激动剂。在本项目中，我们将研究peexrap在脂肪组织重塑中的作用。尽管PexRAP在WAT中大量存在，并且在白色脂肪形成过程中表达增加，但成熟棕色脂肪组织（BAT）中的PexRAP蛋白水平较低。在棕色脂肪形成过程中，peexrap蛋白（而非mRNA）显著减少。自噬抑制稳定了PexRAP蛋白水平，表明PexRAP是BAT发育过程中降解的目标。小鼠peexrap失活促进脂肪细胞褐变，增加能量消耗，减少脂肪，而其在培养细胞中的过表达抑制产热基因的表达。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它作为过氧化物酶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，包括中介复合物的一个成分。基于这些结果，我们假设核定位的peexrap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质储存来编程脂肪组织重塑。为了验证这一假设，我们提出了三个具体目标。在目标1中，我们将研究peexrap降解在产热和能量稳态调节中的生理重要性。在目标2中，我们将评估peexrap在脂肪细胞中的转录调节作用。第三个目标是确定peexrap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稳态中的作用。总之，这项工作将为脂肪组织重塑的分子机制提供重要的见解。了解peexrap及其相关蛋白如何控制脂肪细胞身份对于设计增加棕色和米色脂肪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.