Touchstone Diabetes Center, Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Mol Cell Biol. 2013 Mar;33(5):904-17. doi: 10.1128/MCB.00951-12. Epub 2012 Dec 17.
Hypoxia-inducible factor 1α (HIF1α) 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 HIF1α may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1α 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 HIF1α activation in adipose tissue. HIF1α 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 HIF1α mutant (dn-HIF1α). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1α activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1α inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1α inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.
脂肪细胞中的缺氧诱导因子 1α(HIF1α)诱导是“纤维化反应”的关键组成部分,与缺氧条件下脂肪组织的代谢功能障碍直接相关。我们推断,抑制 HIF1α 可能改善肥胖相关脂肪垫扩张的负面影响。我们使用了选择性 HIF1α 抑制剂 PX-478,其在肿瘤模型中的有效性先前已得到证实。我们证明 PX-478 治疗可有效抑制高脂肪饮食(HFD)诱导的脂肪组织中 HIF1α 的激活。HIF1α 抑制可减少 HFD 小鼠的体重增加,但不会减少正常饮食小鼠的体重增加。治疗可增加能量消耗,并促使其抵抗 HFD 介导的代谢参数恶化。此外,PX-478 治疗可减少脂肪组织中的纤维化和炎症浸润。我们使用脂肪组织特异性、强力霉素诱导的显性负性 HIF1α 突变体(dn-HIF1α)证实了 PX-478 治疗的代谢作用。与药理学结果一致,内源性 HIF1α 活性的遗传抑制可促使 HFD 喂养的小鼠出现类似的代谢改善。总之,我们的结果表明,脂肪细胞中 HIF1α 的抑制可导致显著的代谢改善,这表明脂肪组织中选择性 HIF1α 抑制可能是代谢功能障碍治疗的有效途径。