HDAC9 Knockout Mice Are Protected From Adipose Tissue Dysfunction and Systemic Metabolic Disease During High-Fat Feeding

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 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.

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

“…14 We subsequently determined that HDAC9 is a nutrient sensitive gene whose expression is upregulated in adipocytes from chronically high fat fed, obese mice. 10 Under these conditions, HDAC9 levels fail to decline in preadipocytes during in vitro adipogenic differentiation, suggesting that the regulatory mechanism controlling HDAC9 expression is disrupted in diet-induced obesity. 10 Consequently, the adipogenic differentiation program is blocked, leading to generation of improperly differentiated adipocytes with impaired endocrine function and blunted lipid storage capacity.…”

“…10 Under these conditions, HDAC9 levels fail to decline in preadipocytes during in vitro adipogenic differentiation, suggesting that the regulatory mechanism controlling HDAC9 expression is disrupted in diet-induced obesity. 10 Consequently, the adipogenic differentiation program is blocked, leading to generation of improperly differentiated adipocytes with impaired endocrine function and blunted lipid storage capacity. 10 Importantly, HDAC9 gene deletion removes this block, allowing appropriate activation of the adipogenic differentiation program in adipocytes during chronic high fat feeding.…”

“…12 In lean states, HDAC9 is expressed at high levels in preadipocytes, and its level abruptly falls at the onset of adipogenic differentiation in both humans and mice. 10 Elevating HDAC9 levels by transient transfection prevents adipogenic differentiation, while genetic ablation of HDAC9 accelerates this process, 12 documenting that HDAC9 negatively regulates adipogenic differentiation. HDAC9 gene deletion, however, does not spontaneously activate adipogenic differentiation, suggesting that the abrupt fall in HDAC9 levels is required to prime responsiveness to adipogenic signals.…”

“…We recently demonstrated that preadipocytes isolated from high fat diet-induced obese mice exhibit impaired adipogenic differentiation in vitro, suggesting that differentiation is constrained by factors endogenous to the cells themselves rather than the external environmental. 10 The fact that impaired differentiation persists in vitro, even after several passages in culture, implies an epigenetic mechanism as the probable cause of impaired adipogenic differentiation in high fat diet-induced obesity.…”

“…Indeed, adipocytes that accumulate in obese adipose tissues are inadequately differentiated, exhibiting markedly reduced levels of adipogenic differentiationspecific genes. 10 Defining the causes and consequences of constrained adipogenic differentiation in obesity is a matter of great interest in obesity research. We recently demonstrated that preadipocytes isolated from high fat diet-induced obese mice exhibit impaired adipogenic differentiation in vitro, suggesting that differentiation is constrained by factors endogenous to the cells themselves rather than the external environmental.…”