Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

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.

• Authors: Hirohide Matsuura, Toshihiro Ichiki, Eriko Inoue, Masatoshi Nomura, Ryohei Miyazaki, Toru Hashimoto, Jiro Ikeda, Ryoichi Takayanagi, Guo-Hua Fong, Kenji Sunagawa
• Journal: Circulation (Circulation) Vol. 127 Issue 21 Pg. 2078-87 (May 28 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 23630130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucose Transporter Type 4
• Slc2a4 protein, mouse
• Procollagen-Proline Dioxygenase
• Egln1 protein, mouse
• Hypoxia-Inducible Factor-Proline Dioxygenases
• Glucose

Topics

• Adipocytes (metabolism, pathology)
• Adipose Tissue, White (blood supply, metabolism, pathology)
• Animals
• Cells, Cultured
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Glucose (metabolism)
• Glucose Intolerance (etiology, pathology, physiopathology)
• Glucose Transporter Type 4 (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases
• Lipid Metabolism (physiology)
• Macrophages (pathology)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Muscle, Skeletal (metabolism)
• Neovascularization, Physiologic (physiology)
• Obesity (etiology, pathology, physiopathology)
• Oxygen Consumption (physiology)
• Procollagen-Proline Dioxygenase (deficiency, genetics, physiology)