Our long-range goal is to understand the transcriptional basis of energy homeostasis and how its alteration contributes to obesity and metabolic diseases. Brown fat is a tissue that is specialized in energy expenditure. It is present is adult humans and its activity is inversely associated with human obesity. Thus, brown fat is potentially an attractive therapeutic target tissue for obesity and metabolic diseases. We are interested in how brown fat development and function is regulated by the dynamics of histone methylation and demethylation. We found that promoters of a subset of brown fat genes are methylated at a specific lysine residue of histone H3 in preadipocytes and are demethylated during differentiation. We further identified a demethylase that is responsible for the demethylation during differentiation. We propose that this demethylase-catalyzed removal of histone methylation plays a key role in brown fat determination and metabolism. In the first aim, we will investigate in detail the roles of this demethylase, in particular its demethylation activiy, in brown fat gene expression and brown fat cell metabolism, and whether this demethylase is required for conversion of white adipocytes to brown adipocytes. In the second aim, we will investigate the mechanism by which this demethylase regulates brown fat determination and function. We will perform ChIP-seq to map the occupancy of both this demethylase and its substrate, which will provide us a genome-wide, mechanistic and functional view of this demethylase. In the third aim, we will investigate the in vivo role of this demethylase in brown fa metabolism through both transgenic mice and loss-of-functional studies.

Public Health Relevance

Alterations in pathways that regulate energy balance are responsible for obesity and metabolic diseases. Brown fat is a tissue that is specialized for energy expenditure. Brown fat is present in humans and is inversely correlated with obesity. Our studies address the underlying mechanisms controlling brown fat development and function, which will clearly be very useful for the development of new therapies for obesity and metabolic diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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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 Massachusetts Medical School Worcester
Schools of Medicine
United States
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Pan, Dongning; Mao, Chunxiao; Quattrochi, Brian et al. (2014) MicroRNA-378 controls classical brown fat expansion to counteract obesity. Nat Commun 5:4725
Pan, Dongning; Mao, Chunxiao; Wang, Yong-Xu (2013) Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation. PLoS One 8:e66294
Wei, Ping; Pan, Dongning; Mao, Chunxiao et al. (2012) RNF34 is a cold-regulated E3 ubiquitin ligase for PGC-1ýý and modulates brown fat cell metabolism. Mol Cell Biol 32:266-75
Angione, Alison R; Jiang, Chunhui; Pan, Dongning et al. (2011) PPARýý regulates satellite cell proliferation and skeletal muscle regeneration. Skelet Muscle 1:33
Wang, Yong-Xu (2010) PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res 20:124-37
Pan, Dongning; Fujimoto, Masaki; Lopes, Andrea et al. (2009) Twist-1 is a PPARdelta-inducible, negative-feedback regulator of PGC-1alpha in brown fat metabolism. Cell 137:73-86