Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction
- PMID: 23249949
- PMCID: PMC3623075
- DOI: 10.1128/MCB.00951-12
Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction
Abstract
Hypoxia-inducible factor 1α (HIF1α) induction in adipocytes is a critical component of the "fibrotic response," directly linked to metabolic dysfunction in adipose tissues under hypoxic conditions. We reasoned that inhibition of HIF1α may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1α inhibitor PX-478, whose effectiveness has previously been established in tumor models. We demonstrate that PX-478 treatment effectively suppresses the high-fat-diet (HFD)-induced HIF1α activation in adipose tissue. HIF1α inhibition causes a reduction of weight gain in mice on an HFD but not on a chow diet. Treatment increases energy expenditure and prompts resistance to HFD-mediated deterioration of metabolic parameters. Moreover, PX-478-treated mice have reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. We confirm the metabolic effects obtained with PX-478 treatment using an adipose tissue-specific, doxycycline-inducible dominant negative HIF1α mutant (dn-HIF1α). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1α activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1α inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1α inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.
Figures
![Fig 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620001.gif)
![Fig 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620002.gif)
![Fig 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620003.gif)
![Fig 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620004.gif)
![Fig 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620005.gif)
![Fig 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620006.gif)
![Fig 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620007.gif)
![Fig 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3623075/bin/zmb9991098620008.gif)
Similar articles
-
HIF‑1α: Its notable role in the maintenance of oxygen, bone and iron homeostasis (Review).Int J Mol Med. 2022 Dec;50(6):141. doi: 10.3892/ijmm.2022.5197. Epub 2022 Oct 27. Int J Mol Med. 2022. PMID: 36300198 Review.
-
Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification.Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E338-47. doi: 10.1073/pnas.1515397113. Epub 2015 Dec 31. Proc Natl Acad Sci U S A. 2016. PMID: 26721400 Free PMC article.
-
Fibrosis and adipose tissue dysfunction.Cell Metab. 2013 Oct 1;18(4):470-7. doi: 10.1016/j.cmet.2013.06.016. Epub 2013 Aug 15. Cell Metab. 2013. PMID: 23954640 Free PMC article. Review.
-
Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice.Diabetes. 2011 Oct;60(10):2484-95. doi: 10.2337/db11-0174. Epub 2011 Aug 26. Diabetes. 2011. PMID: 21873554 Free PMC article.
-
Adipose tissue-specific inhibition of hypoxia-inducible factor 1{alpha} induces obesity and glucose intolerance by impeding energy expenditure in mice.J Biol Chem. 2010 Oct 22;285(43):32869-32877. doi: 10.1074/jbc.M110.135509. Epub 2010 Aug 16. J Biol Chem. 2010. PMID: 20716529 Free PMC article.
Cited by
-
Challenges and opportunities in obesity: the role of adipocytes during tissue fibrosis.Front Endocrinol (Lausanne). 2024 Apr 15;15:1365156. doi: 10.3389/fendo.2024.1365156. eCollection 2024. Front Endocrinol (Lausanne). 2024. PMID: 38686209 Free PMC article. Review.
-
Hypoxia, hypoxia-inducible factors and inflammatory bowel diseases.Gastroenterol Rep (Oxf). 2024 Apr 17;12:goae030. doi: 10.1093/gastro/goae030. eCollection 2024. Gastroenterol Rep (Oxf). 2024. PMID: 38638288 Free PMC article. Review.
-
Interleukin-16 is increased in obesity and alters adipogenesis and inflammation in vitro.Front Endocrinol (Lausanne). 2024 Mar 13;15:1346317. doi: 10.3389/fendo.2024.1346317. eCollection 2024. Front Endocrinol (Lausanne). 2024. PMID: 38544694 Free PMC article.
-
PDGFRβ + cell HIF2α is dispensable for white adipose tissue metabolic remodeling and hepatic lipid accumulation in obese mice.Lipids Health Dis. 2024 Mar 20;23(1):81. doi: 10.1186/s12944-024-02069-1. Lipids Health Dis. 2024. PMID: 38509584 Free PMC article.
-
Oxidative Stress, Inflammation, and Mitochondrial Dysfunction: A Link between Obesity and Atrial Fibrillation.Antioxidants (Basel). 2024 Jan 17;13(1):117. doi: 10.3390/antiox13010117. Antioxidants (Basel). 2024. PMID: 38247541 Free PMC article. Review.
References
-
- Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE. 2000. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43: 1498–1506 - PubMed
-
- Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. 2007. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901–911 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases