Epigenetic regulation of adipose development and remodeling

Project Summary/Abstract White adipose tissue has a central role in maintaining whole-body metabolic health. Thus, it is critical to understand how adipocyte develops and how it remodels in response to high caloric diet. Accumulating evidence indicates that epigenetics plays a critical role in orchestrating these processes, however, the mechanisms by which it does so remain largely unknown. In the last funding cycle, we have demonstrated how the enzymatic effectors of DNA methylation regulates multiple aspects of adipose biology, including insulin sensitivity and WAT browning. The goal of this proposal is to better understand how epigenetics controls adipose tissue development and remodeling under chronic nutrition and its impact on metabolism, focusing specifically on TET3, an active DNA demethylase. Consistent with our initial discovery finding an increased Tet3 expression during adipogenesis of naïve APCs, we noted a pro-adipogenic function for TET3 using primary APCs. Moreover, reduced WAT development was observed in mice deficient for Tet3 in APC cells, but not Tet1- or Tet2, nor deficient for Tet3 in mature adipocytes. WAT from Pdgfra-Tet3 KO mice on a high fat diet (HFD) had reduced adipose mass and adipocyte number, with decreased signs of fibro-inflammation, suggesting that Tet3 deficiency prevents unhealthy adipose expansion. Further, these KO mice on HFD dramatically improved insulin resistance and glucose intolerance compared to WT mice. In line with these morphological and metabolic changes in KO mice, our transcription and DNA methylation profiling studies revealed that TET3 targets a defined set of key target genes, including many genes involved in extracellular remodeling (ECM). Based on these novel and exciting preliminary findings, we hypothesize that TET3 is a critical epigenetic regulator of adipocyte development and remodeling by regulating important target genes. To test our hypothesis, Aim1 will firmly establish the role of TET3 function in adipogenesis using various Tet3 conditional knockout and lineage tracing mouse models. Aim2 will elucidate transcriptional and epigenetic basis of TET3 function by the use of transcriptomic and epigenomic approaches. Aim 3 will investigate the TET3 targets critical for adipogenesis and remodeling, and Aim 4 will examine the metabolic consequence of reduced adipogenesis from Tet3 deficiency. Successful completion of the proposed studies will provide novel therapeutic targets for metabolic disorders including obesity and type 2 diabetes.