Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Diabetes. 2011 Oct;60(10):2484-95. doi: 10.2337/db11-0174. Epub 2011 Aug 26.
Obesity, insulin resistance, and type 2 diabetes form a tightly correlated cluster of metabolic disorders in which adipose is one of the first affected tissues. The role of hypoxia and hypoxia-inducible factor 1 (HIF1) in the development of high-fat diet (HFD)-induced obesity and insulin resistance was investigated using animal models.
Mice with adipocyte-specific targeted disruption of the genes encoding the HIF1 obligatory subunits Hif1α or Arnt (Hif1β) were generated using an aP2-Cre transgene with the Cre/LoxP system. The mice were fed an HFD for 12 weeks and their metabolic phenotypes were determined. Gene expression patterns in adipose tissues were also determined by microarray and quantitative PCR.
On an HFD, adipocyte-specific ARNT knockout mice and adipocyte-specific HIF1α knockout mice exhibit similar metabolic phenotypes, including reduced fat formation, protection from HFD-induced obesity, and insulin resistance compared with similarly fed wild-type controls. The cumulative food intake remained similar; however, the metabolic efficiency was lower in adipocyte-specific HIF1α knockout mice. Moreover, indirect calorimetry revealed respiratory exchange ratios were reduced in adipocyte-specific HIF1α knockout mice. Hyperinsulinemic-euglycemic clamp studies demonstrated that targeted disruption of HIF1α in adipocytes enhanced whole-body insulin sensitivity. The improvement of insulin resistance is associated with decreased expression of Socs3 and induction of adiponectin.
Inhibition of HIF1 in adipose tissue ameliorates obesity and insulin resistance. This study reveals that HIF1 could provide a novel potential therapeutic target for obesity and type 2 diabetes.
肥胖、胰岛素抵抗和 2 型糖尿病形成了一组密切相关的代谢紊乱，其中脂肪是最早受影响的组织之一。本研究利用动物模型，探讨了缺氧和缺氧诱导因子 1（HIF1）在高脂肪饮食（HFD）诱导的肥胖和胰岛素抵抗中的作用。
利用 aP2-Cre 转基因和 Cre/LoxP 系统，构建了脂肪细胞特异性敲除 HIF1 必需亚基 Hif1α 或 Arnt（HIF1β）的基因小鼠。将这些小鼠用 HFD 喂养 12 周，然后检测其代谢表型。还通过微阵列和定量 PCR 检测脂肪组织中的基因表达模式。
在 HFD 喂养下，脂肪细胞特异性 ARNT 敲除小鼠和脂肪细胞特异性 HIF1α 敲除小鼠表现出相似的代谢表型，包括脂肪形成减少、对 HFD 诱导的肥胖的保护以及与同等喂养的野生型对照相比的胰岛素抵抗。总的食物摄入量保持相似；然而，脂肪细胞特异性 HIF1α 敲除小鼠的代谢效率较低。此外，间接量热法显示脂肪细胞特异性 HIF1α 敲除小鼠的呼吸交换率降低。高胰岛素-正葡萄糖钳夹研究表明，脂肪细胞中 HIF1α 的靶向敲除增强了全身胰岛素敏感性。胰岛素抵抗的改善与 Socs3 表达的降低和脂联素的诱导有关。
在脂肪组织中抑制 HIF1 可改善肥胖和胰岛素抵抗。本研究表明，HIF1 可能为肥胖和 2 型糖尿病提供一个新的潜在治疗靶点。
