Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance
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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.
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Adipocyte-specific deletion of PHD2 produces mice resistant to HFD-induced obesity and, despite elevated HIF-1α and HIF-2α, improved glucose tolerance and insulin sensitivity.
“In contrast, adipocyte-specific deletion of PHD2 produces mice that are resistant to HFD-induced obesity and, despite elevated levels of both HIF-1α and HIF-2α, the mice display improved glucose tolerance and insulin sensitivity (7).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [7]
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- Authors
- Matsuura, H., Ichiki, T., Inoue, E., Nomura, M., Miyazaki, R., Hashimoto, T., Ikeda, J., Takayanagi, R., Fong, G.-H., & Sunagawa, K.
- Affiliations
- Kyushu University (JP)
- Venue
- Circulation
- Published
- 2013-05-28
- Volume
- 127
- Issue
- 21
- Pages
- 2078-2087
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W1991947510
- Cited by
- 77
- References
- 40
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 3 · 2014: 6 · 2013: 1
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- SENSHIN Medical Research Foundation
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- PHD2, diet-induced obesity, impaired glucose tolerance, hypoxia-inducible factor, oxygen sensing, adipocytes, white adipose tissue, insulin resistance, macrophage infiltration, adiponectin, glycolytic enzymes, brown adipose tissue, UCP1, lipid accumulation, high-fat diet
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Glucose, Macrophages, Mice, Transgenic, Obesity, Oxygen Consumption, Procollagen-Proline Dioxygenase, Adipocytes, Glucose Intolerance, Mice, Knockout, Muscle, Skeletal, Neovascularization, Physiologic, Lipid Metabolism, Glucose Transporter Type 4, Mice, Adipose Tissue, White, Diet, High-Fat, Hypoxia-Inducible Factor-Proline Dioxygenases
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