HDAC9 Knockout Mice Are Protected From Adipose Tissue Dysfunction and Systemic Metabolic Disease During High-Fat Feeding
- Tapan K. Chatterjee1⇑,
- Joshua E. Basford2,
- Ellen Knoll1,
- Wilson S. Tong1,
- Victor Blanco3,
- Andra L. Blomkalns3,
- Steven Rudich4,
- Alex B. Lentsch4,
- David Y. Hui2 and
- Neal L. Weintraub1
- 1Department of Internal Medicine, Division of Cardiovascular Diseases, University of Cincinnati, Cincinnati, OH
- 2Department of Pathology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- 3Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH
- 4Department of Surgery, University of Cincinnati, Cincinnati, OH
- Corresponding author: Tapan K. Chatterjee, .
During chronic caloric excess, adipose tissue expands primarily by enlargement of individual adipocytes, which become stressed with lipid overloading, thereby contributing to obesity-related disease. Although adipose tissue contains numerous preadipocytes, differentiation into functionally competent adipocytes is insufficient to accommodate the chronic caloric excess and prevent adipocyte overloading. We report for the first time that a chronic high-fat diet (HFD) impairs adipogenic differentiation, leading to accumulation of inefficiently differentiated adipocytes with blunted expression of adipogenic differentiation-specific genes. Preadipocytes from these mice likewise exhibit impaired adipogenic differentiation, and this phenotype persists during in vitro cell culture. HFD-induced impaired adipogenic differentiation is associated with elevated expression of histone deacetylase 9 (HDAC9), an endogenous negative regulator of adipogenic differentiation. Genetic ablation of HDAC9 improves adipogenic differentiation and systemic metabolic state during an HFD, resulting in diminished weight gain, improved glucose tolerance and insulin sensitivity, and reduced hepatosteatosis. Moreover, compared with wild-type mice, HDAC9 knockout mice exhibit upregulated expression of beige adipocyte marker genes, particularly during an HFD, in association with increased energy expenditure and adaptive thermogenesis. These results suggest that targeting HDAC9 may be an effective strategy for combating obesity-related metabolic disease.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1148/-/DC1.
T.K.C. and N.L.W. are currently affiliated with the Department of Internal Medicine, Vascular Biology Center, Georgia Regents University, Augusta, GA.
- Received July 24, 2013.
- Accepted September 30, 2013.
- © 2014 by the American Diabetes Association.
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