Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Cell Metab. 2011 Oct 5;14(4):491-503. doi: 10.1016/j.cmet.2011.08.006.
In obesity, adipocytes distant from vasculature become hypoxic and dysfunctional. This hypoxic response is mediated by hypoxia-inducible factors (Hif1α, Hif2α, and Hif3α) and their obligate partner, Hif1β (Arnt). We show that mice lacking Hif1β in fat (FH1βKO) are lean, exhibit reduced adipocyte size, and are protected from age- and diet-induced glucose intolerance. There is also reduced Vegf and vascular permeability in FH1βKO fat, but diet-induced inflammation and fibrosis is unchanged. Adipocytes from FH1βKO mice have reduced glucose uptake due to decreased Glut1 and Glut4, which is mirrored in 3T3-L1 adipocytes with Hif1β knockdown. Hif1β knockdown cells also fail to respond appropriately to hypoxia with reduced cellular respiration and reduced mitochondrial gene expression. Some, but not all, of these effects are reproduced by Hif1α knockdown. Thus, Hif1β/Arnt regulates glucose uptake, mitochondrial gene expression, and vascular permeability to control adipose mass and function, providing a target for obesity therapy.
在肥胖症中，远离血管的脂肪细胞会缺氧并出现功能障碍。这种缺氧反应是由缺氧诱导因子 (Hif1α、Hif2α 和 Hif3α) 及其必需伴侣 Hif1β (Arnt) 介导的。我们发现脂肪组织中缺乏 Hif1β 的小鼠 (FH1βKO) 体型偏瘦，脂肪细胞体积减小，并且能够抵抗年龄和饮食引起的葡萄糖不耐受。FH1βKO 脂肪组织中的 Vegf 和血管通透性也降低，但饮食引起的炎症和纤维化没有变化。FH1βKO 小鼠的脂肪细胞由于 Glut1 和 Glut4 的减少而导致葡萄糖摄取减少，这在 Hif1β 敲低的 3T3-L1 脂肪细胞中得到了体现。Hif1β 敲低细胞对缺氧的反应也不适当，细胞呼吸和线粒体基因表达减少。这些影响中的一些（但不是全部）可以通过 Hif1α 敲低来重现。因此，Hif1β/Arnt 调节葡萄糖摄取、线粒体基因表达和血管通透性，以控制脂肪量和功能，为肥胖症治疗提供了一个靶点。
