Journal
JCI INSIGHT
Volume 3, Issue 15, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.120159
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Funding
- NIH [HL116848, HL127240, AG043822, T32HL007822, F32HL126354, R01HL133230, R01 DK103056]
- American Heart Association (AHA) [16SFRN31400013]
- Canadian Institutes of Health Research [FRN-216927]
- AHA postdoctoral fellowship [16POST30960017]
- Boettcher Foundation
- AHA [13SDG17400031]
- University of Colorado Department of Medicine Outstanding Early Career Scholar Program
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Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit enhanced thermogenic potential and, in response to high-fat feeding, attenuated obesity, improved insulin sensitivity, and reduced hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to beta-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. These findings define an epigenetic pathway for the regulation of energy homeostasis and suggest the potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.
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