HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding

Tapan K. Chatterjee, Joshua E. Basford, Ellen Knoll, Wilson S. Tong, Victor Blanco, Andra L. Blomkalns, Steven Rudich, Alex B. Lentsch, David Y. Hui, Neal L. Weintraub

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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 differentiationspecific 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.

Original languageEnglish (US)
Pages (from-to)176-187
Number of pages12
JournalDiabetes
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Chatterjee, T. K., Basford, J. E., Knoll, E., Tong, W. S., Blanco, V., Blomkalns, A. L., Rudich, S., Lentsch, A. B., Hui, D. Y., & Weintraub, N. L. (2014). HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding. Diabetes, 63(1), 176-187. https://doi.org/10.2337/db13-1148