Metabolic disorders such as type II diabetes, obesity, and cardiovascular disease are reaching epidemic levels worldwide. These metabolic diseases lead to an array of debilitating co-morbidities and contribute significantly to growing healthcare costs. Thus, renewed focus and new approaches towards developing therapeutic interventions are needed. Activation or enhancement of brown adipose tissue function represents such an intervention, as it possesses intrinsic calorie-burning function through its professional lipid and glucose oxidation abilities. We have recently discovered that the Class I histone deacetylase 3 (HDAC3), a pharmacologically targetable enzyme, is a key epigenomic mediator that enhances brown adipose tissue function through an unknown mechanism. In metabolic tissues such as the liver, HDAC3 mediates its epigenomic effects on lipogenic genes through the circadian nuclear receptor Rev-erba. However, our new genetic evidence suggests HDAC3 has Rev-erba-independent mechanisms modulating brown adipose tissue function through incompletely understood mechanisms. I hypothesize that HDAC3 is modulating critical metabolic pathways to enhance thermogenesis and cold adaptation through an unknown transcription factor.
The first aim of this proposal will elucidate the physiological and functional requirement of HDAC3 on brown adipose mediated cold tolerance, cold adaptation, energy metabolism, and glucose and lipid homeostasis using tissue specific loss-of-function genetic mouse models as well as primary cell culture systems. I will intersect these physiological findings with changes in the transcriptome to establish gene pathways and networks modulated by HDAC3.
The second aim of this proposal will determine the transcription factor through which HDAC3 mediates its epigenomic function. Specifically, I will use chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq) to determine genomic sites of HDAC3 enrichment. The nearest genes will be integrated with transcriptome data to determine functional HDAC3 sites. The identified sites will allow for motif analysis and subsequent identification of the transcriptin factor mediating HDAC3 functions. Thus, elucidating the physiological and functional role of HDAC3 in brown adipose tissue, as well as the factor by which these effects are mediated through, will significantly enhance our understanding of brown adipose tissue biology, thermogenesis, and calorie burning metabolic pathways. Determining the mechanism by which HDAC3 modulates the brown adipose epigenome may allow for tailored therapeutics to manipulate and increase energy expending pathways in order to combat metabolic diseases.

Public Health Relevance

The prevalence of metabolic disorders such as obesity, type II diabetes, and cardiovascular disease are rapidly increasing in the developed world. Brown adipose tissue is a highly metabolic tissue and significant contributor to total body energy expenditure, making it an attractive target tissue for therapeutic intervention in metabolic disease. When recruited to the genome, histone deacetylase 3 (HDAC3) acts as a key epigenomic modulator of brown adipose tissue function. The goal of this proposal is to elucidate both the mechanism of genomic recruitment and the physiological requirement of HDAC3 for brown adipose function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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