HDAC11 suppresses the thermogenic program of adipose tissue via BRD2
Rushita A. Bagchi, … , Edward Seto, Timothy A. McKinsey
Rushita A. Bagchi, … , Edward Seto, Timothy A. McKinsey
Published August 9, 2018
Citation Information: JCI Insight. 2018;3(15):e120159. https://doi.org/10.1172/jci.insight.120159.
View: Text | PDF
Research Article Metabolism

HDAC11 suppresses the thermogenic program of adipose tissue via BRD2

Abstract

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 β-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.

Authors

Rushita A. Bagchi, Bradley S. Ferguson, Matthew S. Stratton, Tianjing Hu, Maria A. Cavasin, Lei Sun, Ying-Hsi Lin, Dianxin Liu, Pilar Londono, Kunhua Song, Maria F. Pino, Lauren M. Sparks, Steven R. Smith, Philipp E. Scherer, Sheila Collins, Edward Seto, Timothy A. McKinsey

×

Figure 1

HDAC11 deficiency increases thermogenic potential in mice.

Options: View larger image (or click on image) Download as PowerPoint
HDAC11 deficiency increases thermogenic potential in mice. (A) Gross mor...
(A) Gross morphology of 10-week-old male WT and Hdac11–/– (KO) littermates fed standard rodent chow. (B–D) iBAT, ingWAT, and eWAT from 10-week-old male mice were dissected and weighed. n = 4 WT, n = 5 KO. (E and F) qPCR analysis of Hdac11 mRNA expression in mouse and human BAT and WAT. E: n = 4, BAT and WAT, ; F: n = 6 BAT, n = 9 WAT. (G) WT and KO mice were fed standard rodent chow and exposed to 4°C for 24 hours, and core body temperature was recorded at the indicated time points using a rectal thermal probe; n = 4 mice/group. (H and I) Oxygen consumption (VO2) and metabolic rate (MR) were measured using a CLAMS system for 24 hours. (J) Activity was calculated using laser beam breaks per 24 hours. H–J: n = 4 mice/group. (K) H&E staining of iBAT after 24 hours of 4°C exposure. Scale bar: 50 μm. (L and M) Quantitative PCR analysis of Ucp1 and Pgc1α mRNA expression in iBAT from mice housed at room temperature (RT) or exposed to 4°C for 24 hours; n = 4 mice/group. (N) H&E staining and UCP1 immunohistochemistry of ingWAT 24 hours after 4°C exposure. Arrows indicate evidence of beiging. Scale bars: 50 μm. (O) qPCR analysis of Ucp1 mRNA expression in ingWAT; n = 4 mice/group. (P) Immunoblot analysis of UCP1 protein expression in ingWAT. (Q) qPCR analysis of Pgc1α mRNA expression in ingWAT; n = 4 mice/group. Values for all graphs represent mean ± SEM; *P < 0.05 vs. WT (or BAT for E and F), #P < 0.05 vs. WT 4°C using ANOVA with Tukey’s multiple-comparisons test. Student’s t test was employed for 2 groups, and †P < 0.05 vs. WT RT; unpaired Student’s t test was employed for 2 groups, after ANOVA indicated significance.