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

Abstract

Hypoxia-inducible factor 1␣ (HIF1␣) 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␣ may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1␣ 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␣ activation in adipose tissue. HIF1␣ 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␣ mutant (dn-HIF1␣). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1␣ activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1␣ inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1␣ inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

“…PX-478 has been shown to decrease Hif1α both in vitro and in vivo by decreasing Hif1α mRNA levels and blocking Hif1α mRNA translation (27,30,31). Constitutive VEGF signaling abrogates the effect of PX-478 on downstream angiogenic signaling, confirming that its effect is upstream of VEGF.…”

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

“…Consistently, several studies point to the role of macrophages in promoting fibroblastic phenotype and ECM production in human preadipocytes [33][34][35] . Taken together with recent observations that activation of hypoxia-inducible factor-1 in adipocytes contributes to interstitial fibrosis in adipose tissue 8 , Mincle in macrophages may link obesity-induced adipocyte damages with myofibroblast formation.…”

“…In this regard, Khan et al 6 reported that mice lacking collagen VI, which is expressed abundantly in adipose tissue, exhibit the uninhibited adipose tissue expansion and substantial improvement in insulin sensitivity on a high-fat diet (HFD). Although recent evidence suggests a role for obesity-induced hypoxic state 7,8 , the molecular mechanisms underlying adipose tissue fibrosis are still largely unknown.…”

HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

“…Inhibition of Hif-1a by disruption of its gene in adipocytes (30) or administration of its inhibitor (31) or antisense oligonucleotides (32) attenuates the consequences of an HFD in mice. Currently, no explanation is available for the discrepancy between those data and the beneficial effects of Hif-a stabilization by Hif-p4h-2 deficiency, but the additional stabilization of Hif-2a has been suggested to possibly play an important role (25).…”