Abstract 17732: Histone Deacetylase Knockout Mice are Protected From Adipose Tissue Dysfunction and Systemic Metabolic Disease During High Fat Feeding
Background: Obesity-related insulin resistance and diabetes is a leading cause of heart disease. In obesity, adipose tissue expands primarily by adipocyte hypertrophy rather than adipocyte hyperplasia (formation of new adipocytes via differentiation of preadipocytes), which contributes to the adverse metabolic state. We recently identified histone deacetylase-9 (HDAC9) as a novel endogenous inhibitor of preadipocyte differentiation.
Objectives: Test the hypothesis that differentiation of preadipocytes is impaired in high fat fed- (HF) mice through an HDAC9-dependent mechanism, thus contributing to obesity-related disease.
Methods: Male mice [8 week old wild type (wt) and HDAC9-/-] were placed on chow diet or switched to a HF diet (60% calories from fat) for 12 weeks. Metabolic phenotyping was performed, mice were euthanized, and tissues and blood were collected for analysis. Differentiation of preadipocytes from inguinal subcutaneous depot was compared in chow- and HF-fed mice.
Results: In HF-fed wt mice, differentiation of preadipocytes was markedly impaired, as evidenced by reduced expression of adipogenic differentiation-specific genes and lipid droplet accumulation, while HDAC9 expression remained elevated. HDAC9 gene deletion did not affect caloric consumption but prevented HF-induced impaired adipogenic differentiation. Moreover, HF-fed HDAC9 -/- mice exhibited diminished weight gain, reduced adipose tissue inflammation and hepatic steatosis, and improved glucose tolerance/insulin sensitivity. HDAC9 -/- mice also exhibited increased energy expenditure and adaptive thermogenesis. Locomotion and brown fat phenotype were unaltered in HDAC9-/- mice, while expression of beige adipocyte marker genes was strongly upregulated in white adipose tissue (WAT).
Conclusions: Chronic HF diet impairs adipogenic differentiation through a mechanism involving HDAC9, thus contributing to adipocyte overloading and adipose tissue inflammation. Ablation of HDAC9 prevented these effects and enhanced expression of beige adipocyte genes in WAT, thus modulating weight gain and metabolic outcome. These novel findings suggest that targeting HDAC9 may be an effective strategy for combating obesity-related metabolic disease.
- © 2013 by American Heart Association, Inc.