Obesity is a global health epidemic associated with several metabolic diseases, such as type 2 diabetes. While white adipose tissue (WAT) accumulates fat as energy storage that in excess results in obesity, brown adipose tissue (BAT) dissipates energy as heat via non-shivering thermogenesis. Recently, substantial functional BAT has been proven to be present even in adult humans-a finding which has generated considerable interest, since an increase in BAT activity may be protective against obesity. Inducing thermogenic genes such as uncoupling protein-1 (UCP1) and promoting BAT development could be therapeutic strategies for obesity. Thus, it is critical to elucidate the BAT transcriptional network. We have identified a novel zinc finger transcription factor, B2, which is preferentially expressed in BAT compared to WAT and other tissues and is induced drastically upon cold exposure. We found that B2 directly binds to and robustly activates the UCP1 promoter. The putative B2 binding element is found in the promoter regions of other BAT-enriched genes, and we detected binding and activation of PGC1? promoter by B2. B2 expression is increased during brown adipocyte differentiation. We found that constitutive expression of B2 enhances brown adipocyte differentiation, whereas shRNA knockdown inhibits differentiation. The B2 knockout mice that we have generated show drastically decreased BAT mass with abnormal brown adipocyte morphology and decreased expression of UCP1 and other BAT-enriched genes. The goal of this research is to understand how B2 activates UCP1 and other BAT genes and the role of B2 in the BAT development and function.
Aim 1 is to examine the molecular mechanisms underlying B2 activation of UCP1 and other BAT-enriched genes and how B2 is induced upon cold exposure.
Aim 2 is to investigate the role of B2 in brown adipocyte differentiation in vitro.
Aim 3 is to employ gain- and loss-of function approaches in mice to examine the function of B2 in vivo. This research will contribute to the emerging field of BAT biology and may provide new targets for obesity therapeutics.

Public Health Relevance

While white adipose tissue stores fat to increase adiposity, brown adipose tissue dissipates energy as heat for thermogenesis. This research is directed toward understanding the function of a brown adipocyte transcription factor that governs brown adipose tissue gene expression and development. Understanding the mechanism and signaling pathway for the action of this transcription factor will provide us novel targets to develop strategies to control obesity and associated diseases such as diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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University of California Berkeley
Schools of Earth Sciences/Natur
United States
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Sambeat, Audrey; Gulyaeva, Olga; Dempersmier, Jon et al. (2017) Epigenetic Regulation of the Thermogenic Adipose Program. Trends Endocrinol Metab 28:19-31
Sambeat, Audrey; Gulyaeva, Olga; Dempersmier, Jon et al. (2016) LSD1 Interacts with Zfp516 to Promote UCP1 Transcription and Brown Fat Program. Cell Rep 15:2536-49
Dempersmier, Jon; Sul, Hei Sook (2015) Shades of brown: a model for thermogenic fat. Front Endocrinol (Lausanne) 6:71
Dempersmier, Jon; Sambeat, Audrey; Gulyaeva, Olga et al. (2015) Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat. Mol Cell 57:235-46