Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-induced Obesity and Glucose Intolerance
Background—Recent studies suggest that oxygen-sensing pathway consisting of transcription factor hypoxia inducible factor (HIF) and prolyl hydroxylase domain proteins (PHD) 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 adipocyte affects diet-induced obesity and associated metabolic abnormalities.
Methods and Results—To delete PHD2 in adipocyte, PHD2-floxed mice were crossed with aP2-Cre transgenic mice (Phd2f/f/aP2-Cre). Phd2f/f/aP2-Cre mice were resistant to high-fat diet-induced obesity (36.7 ± 1.7g vs 44.3 ± 2.0g in control, P<0.01) and showed better glucose tolerance and HOMA-IR index (3.6±1.0 vs 11.1±2.1 in control, P<0.01) than control mice. The weight of white adipose tissue (WAT) was lighter (epididymal fat: 758 ± 35mg vs. 1208 ± 507mg in control, P<0.01) with reduction of adipocyte size. Macrophage infiltration into WAT was also alleviated in Phd2f/f/aP2-Cre mice. Target genes of HIF including glycolytic enzymes and adiponectin were upregulated in adipocytes of Phd2f/f/aP2-Cre mice. Lipid content was decreased and uncoupling protein 1 expression was increased in brown adipose tissue of Phd2f/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 up-regulation of glycolytic enzymes and reduced lipid accumulation.
Conclusions—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.
- Received January 31, 2013.
- Revision received April 8, 2013.
- Accepted April 18, 2013.