Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation.
Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation.
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DOI：
10.1128/mcb.00430-15
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发表时间：
2016-02-01
影响因子：
5.3
通讯作者：
Chavakis T
中科院分区：
文献类型：
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作者：
García-Martín R;Alexaki VI;Qin N;Rubín de Celis MF;Economopoulou M;Ziogas A;Gercken B;Kotlabova K;Phieler J;Ehrhart-Bornstein M;Bornstein SR;Eisenhofer G;Breier G;Blüher M;Hampe J;El-Armouche A;Chatzigeorgiou A;Chung KJ;Chavakis T
血管生成是肥胖过程中白色（WAT）和棕色（BAT）脂肪组织适应的中心调节因子。本研究表明，脂肪细胞（通过Fabp4-Cre转基因小鼠）中缺氧诱导因子2α (HIF2α)的缺失，而髓细胞或内皮细胞中不存在HIF2α的缺失，会对WAT血管生成产生负面影响，并促进WAT炎症、WAT功能障碍、肝成骨病和肥胖症的全身胰岛素抵抗。重要的是，脂肪细胞HIF2α调节肥胖BAT的血管内皮生长因子（VEGF）表达和血管生成及其产热功能。一致地，肥胖脂肪细胞特异性hif2 α-缺陷小鼠表现出BAT失调，与解偶联蛋白1 （UCP1）水平降低和对冷暴露的功能失调产热反应有关。VEGF可逆转脂肪细胞hif2 α-缺陷小鼠的WAT和BAT炎症及BAT功能障碍。总之，我们的研究结果表明，脂肪细胞HIF2α通过促进WAT和BAT的血管生成以及抵消肥胖介导的BAT功能障碍，可以防止肥胖和代谢失调的不适应。
Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction.