REGULATION OF ADIPOSE TISSUE REMODELING AND ENERGY HOMEOSTASIS

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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.