Obesity and diabetes have reached epidemic proportions in our society. Brown adipose tissue (BAT), which burns fat to produce heat, represents a promising target to combat these diseases. We have recently discovered that his tone deacetylase 3 (HDAC3), an enzymatic modulator of the epigenome, regulates critical lipid metabolism genes in BAT. I hypothesize that manipulation of HDAC3 in brown adipose will improve metabolic function. My first specific aim is to characterize HDAC3-dependent transcriptional regulation in BAT to determine which gene networks are controlled by HDAC3 under basal conditions and following cold exposure. Factors mediating HDAC3 recruitment to these genes will be identified in genome-wide analyses, and validated by gain and loss-of-function studies. My second specific aim is to investigate the physiological role of HDAC3 in BAT bioenergetics processes. I will examine the impact of HDAC3 on lipid metabolism, mitochondrial uncoupling capacity, and cold tolerance in cells and live animals. The proposed experiments will address the epigenetic and transcriptional mechanisms by which HDAC3 regulates organism energy expenditure. The results of this study will advance the basic understanding of how mammals cope with environmental stresses through coordinated changes in bioenergetics networks. Furthermore, this work has the potential to translate into novel therapies targeting conserved, fat-burning pathways for the prevention and treatment of metabolic disorders.

Public Health Relevance

Obesity and diabetes have reached epidemic proportions in our society. The goal of the proposed research is to more completely understand the regulation of fundamental, fat-burning processes in an effort to develop novel therapies with which to combat these metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK095563-01A1
Application #
8456819
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Castle, Arthur
Project Start
2012-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$49,214
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gerhart-Hines, Zachary; Lazar, Mitchell A (2015) Circadian metabolism in the light of evolution. Endocr Rev 36:289-304
Gerhart-Hines, Z; Lazar, M A (2015) Rev-erbα and the circadian transcriptional regulation of metabolism. Diabetes Obes Metab 17 Suppl 1:12-6
Fang, Bin; Everett, Logan J; Jager, Jennifer et al. (2014) Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo. Cell 159:1140-52
Gerhart-Hines, Zachary; Feng, Dan; Emmett, Matthew J et al. (2013) The nuclear receptor Rev-erbα controls circadian thermogenic plasticity. Nature 503:410-3