Abstract 14211: Adipocyte-Specific Deletion of Prolyl Hydroxylase Domain Protein 2 Ameliorates Diet-Induced Obesity and Glucose Intolerance in Mice
Objective: Oxygen sensing pathway consists of hypoxia inducible factor (HIF) and prolyl hydroxylase domain proteins (PHD). PHD catalyzes oxygen-dependent hydroxylation of specific proline residues in HIF-α subunit, followed by ubiquitination and subsequent proteasomal degradation. Hypoxia inhibits PHD activities and thereby increases the level of HIF-α. Recent studies suggest that oxygen sensing pathway plays an important role in glucose metabolism. However, the role of adipocyte PHD in glucose metabolism and development of obesity has not been clarified. We examined whether adipocyte-specific deletion of PHD2, the main oxygen sensor, affects obesity and associated metabolic abnormalities.
Methods and Results: Adipocyte-specific PHD2-deficient (AdipoPHD2KO) mice were created by crossing PHD2-floxed mice with aP2-Cre transgenic mice and morphological, molecular and metabolic analyses were performed. AdipoPHD2KO mice were resistant to high-fat diet-induced obesity (p<0.01) and showed better glucose tolerance and insulin sensitivity, and consumed more oxygen than control mice (p<0.05). The weight of white adipose tissue (WAT) was lighter (p<0.01) with reduction of adipocytes size (p<0.01), and macrophage infiltration was alleviated in white adipose tissue (WAT) of AdipoPHD2KO mice (p<0.01). HIF-1α and HIF-2α proteins were accumulated, and multiple HIF-target genes including glycolytic enzymes and glucose transporter 1, and adiponectin were upregulated in WAT of AdipoPHD2KO mice (p<0.05). In brown adipose tissue of AdipoPHD2KO mice, lipid content was decreased (p<0.05) and uncoupling protein 1 expression was increased (p<0.05). 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 (p<0.01) and reduced lipid accumulation of in the cytosol (p<0.05).
Conclusions: PHD2 deletion in adipocytes ameliorates diet-induced obesity and glucose intolerance, which may be mediated by an increase in glucose consumption through activation of glycolytic pathway. Adipocyte-specific manipulation of PHD2 might be a novel strategy for the treatment for obesity and metabolic abnormalities.
- © 2011 by American Heart Association, Inc.