Adipose tissue remodeling, involving adipogenesis, lipogenesis, lipolysis, extracellular matrix (EM) remodeling, and thermogenesis, plays a central role in regulating energy homeostasis. A notable adaptive process within adipose tissues is the ?browning? or ?beiging? of white adipose tissue (WAT): enhanced brown/beige fat function is accompanied by a substantial improvement in metabolic health, including increased glucose tolerance and insulin sensitivity as well as reduced adipose tissue inflammation and fibrosis. Reciprocally, dysregulation in the processes is tightly associated with obesity and type 2 diabetes. As such, a better understanding of the brown/beige fat biogenesis continues to be a significant area of research in the field of metabolic disorders. The best-known stimuli of brown/beige fat biogenesis are cold and PPAR?: cold exposure via activation of ?-adrenoceptor (?-AR) or chronic treatment with synthetic PPAR? ligands (e.g., thiazolidinediones) activate the brown/beige fat-selective genetic program. However, chronic activation of these pathways often causes multiple side effects, such as cardiovascular diseases. Thus, identifying alternative pathways that selectively stimulate brown/beige fat biogenesis, while avoiding the detrimental effects of the conventional pathways, may promise new approaches that improve metabolic health with minimal side effects. In this regard, our recent finding may offer a new opportunity: we identified a previously uncharacterized cell-intrinsic post-translational pathway that activates brown/beige fat biogenesis ? e.g., enhanced mitochondrial biogenesis, fatty acid oxidation, thermogenesis, as well as reduced adipose tissue inflammation and fibrosis ? without activating the canonical PPAR? transcription pathway. We found the first ubiquitin E3-ligase complex that controls the protein stability of PRDM16, a dominant transcriptional co-activator of the brown/beige fat gene program. Notably, inhibition of the ubiquitin E3-ligase complex is sufficient to activate the brown/beige fat program through extending the half-life of PRDM16 protein. Accordingly, this proposal aims to determine the post-translational mechanisms through which the newly identified E3-ligase complex for PRDM16 regulateswhole-body energy metabolism.

Public Health Relevance

Enhanced brown/beige fat biogenesis is associated with a substantial improvement in metabolic health; however, how this process is regulated remain insufficiently understood. Building upon our recent discovery of a novel ubiquitin E3-ligase complex that controls the protein stability of PRDM16, a dominant transcriptional regulator of brown/beige fat biogenesis, this proposal aims to understand the physiological role and biochemical mechanisms through which the E3-ligase complex controls whole-body energy metabolism. The work resulting from this application will establish a new roadmap to improve metabolic health through the post- translational control of PRDM16, while avoiding side effects that are associated with conventional brown/beige fat activators, such as cold and PPAR? agonists.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Haft, Carol R
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Beth Israel Deaconess Medical Center
United States
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