Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Circulation. 2013 May 28;127(21):2078-87. doi: 10.1161/CIRCULATIONAHA.113.001742. Epub 2013 Apr 29.
Recent studies suggest that the oxygen-sensing pathway consisting of transcription factor hypoxia-inducible factor and prolyl hydroxylase domain proteins (PHDs) plays a critical role in glucose metabolism. However, the role of adipocyte PHD in the development of obesity has not been clarified. We examined whether deletion of PHD2, the main oxygen sensor, in adipocytes affects diet-induced obesity and associated metabolic abnormalities.
To delete PHD2 in adipocyte, PHD2-floxed mice were crossed with aP2-Cre transgenic mice (Phd2(f/f)/aP2-Cre). Phd2(f/f)/aP2-Cre mice were resistant to high-fat diet-induced obesity (36.7±1.7 versus 44.3±2.0 g in control; P<0.01) and showed better glucose tolerance and homeostasis model assessment-insulin resistance index than control mice (3.6±1.0 versus 11.1±2.1; P<0.01). The weight of white adipose tissue was lighter (epididymal fat, 758±35 versus 1208±507 mg in control; P<0.01) with a reduction in adipocyte size. Macrophage infiltration into white adipose tissue was also alleviated in Phd2(f/f)/aP2-Cre mice. Target genes of hypoxia-inducible factor, including glycolytic enzymes and adiponectin, were upregulated in adipocytes of Phd2(f/f)/aP2-Cre mice. Lipid content was decreased and uncoupling protein-1 expression was increased in brown adipose tissue of Phd2(f/f)/aP2-Cre mice. Knockdown of PHD2 in 3T3L1 adipocytes induced a decrease in the glucose level and an increase in the lactate level in the supernatant with upregulation of glycolytic enzymes and reduced lipid accumulation.
PHD2 in adipose tissue plays a critical role in the development of diet-induced obesity and glucose intolerance. PHD2 might be a novel target molecule for the treatment of obesity and associated metabolic abnormalities.
最近的研究表明，由转录因子缺氧诱导因子和脯氨酰羟化酶结构域蛋白（PHD）组成的氧感应通路在葡萄糖代谢中起着关键作用。然而，脂肪细胞中 PHD 的作用在肥胖的发展中尚未阐明。我们研究了脂肪细胞中主要氧传感器 PHD2 的缺失是否会影响饮食诱导的肥胖和相关代谢异常。
为了在脂肪细胞中删除 PHD2，将 PHD2 基因敲除小鼠与 aP2-Cre 转基因小鼠（Phd2(f/f)/aP2-Cre）杂交。Phd2(f/f)/aP2-Cre 小鼠对高脂肪饮食诱导的肥胖具有抗性（对照组为 36.7±1.7 克，而 Phd2(f/f)/aP2-Cre 组为 44.3±2.0 克；P<0.01），且葡萄糖耐量和稳态模型评估-胰岛素抵抗指数优于对照组（3.6±1.0 对 11.1±2.1；P<0.01）。白色脂肪组织的重量较轻（附睾脂肪，对照组为 758±35 毫克，Phd2(f/f)/aP2-Cre 组为 1208±507 毫克；P<0.01），脂肪细胞体积减小。Phd2(f/f)/aP2-Cre 小鼠的白色脂肪组织中巨噬细胞浸润也减轻。缺氧诱导因子的靶基因，包括糖酵解酶和脂联素，在 Phd2(f/f)/aP2-Cre 小鼠的脂肪细胞中上调。Phd2(f/f)/aP2-Cre 小鼠的棕色脂肪组织中脂质含量降低，解偶联蛋白-1 表达增加。3T3L1 脂肪细胞中 PHD2 的敲低导致上清液中的葡萄糖水平降低，乳酸水平升高，同时糖酵解酶上调，脂质积累减少。
脂肪组织中的 PHD2 在饮食诱导的肥胖和葡萄糖不耐受的发展中起着关键作用。PHD2 可能是肥胖和相关代谢异常治疗的新靶分子。
