Selective Inhibition of Hypoxia-Inducible Factor 1α Ameliorates Adipose Tissue Dysfunction

Hypoxia-inducible factor 1 alpha (HIF1 alpha) induction in adipocytes is a critical component of the "fibrotic response," directly linked to metabolic dysfunction in adipose tissues under hypoxic conditions. We reasoned that inhibition of HIF1 alpha may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1 alpha inhibitor PX-478, whose effectiveness has previously been established in tumor models. We demonstrate that PX-478 treatment effectively suppresses the high-fat-diet (HFD)-induced HIF1 alpha activation in adipose tissue. HIF1 alpha inhibition causes a reduction of weight gain in mice on an HFD but not on a chow diet. Treatment increases energy expenditure and prompts resistance to HFD-mediated deterioration of metabolic parameters. Moreover, PX-478-treated mice have reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. We confirm the metabolic effects obtained with PX-478 treatment using an adipose tissue-specific, doxycycline-inducible dominant negative HIF1 alpha mutant (dn-HIF1 alpha). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1 alpha activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1 alpha inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1 alpha inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.