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The differential role of Hif1?/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation.

ABSTRACT: In obesity, adipocytes distant from vasculature become hypoxic and dysfunctional. This hypoxic response is mediated by hypoxia-inducible factors (Hif1?, Hif2?, and Hif3?) and their obligate partner, Hif1? (Arnt). We show that mice lacking Hif1? in fat (FH1?KO) are lean, exhibit reduced adipocyte size, and are protected from age- and diet-induced glucose intolerance. There is also reduced Vegf and vascular permeability in FH1?KO fat, but diet-induced inflammation and fibrosis is unchanged. Adipocytes from FH1?KO mice have reduced glucose uptake due to decreased Glut1 and Glut4, which is mirrored in 3T3-L1 adipocytes with Hif1? knockdown. Hif1? knockdown cells also fail to respond appropriately to hypoxia with reduced cellular respiration and reduced mitochondrial gene expression. Some, but not all, of these effects are reproduced by Hif1? knockdown. Thus, Hif1?/Arnt regulates glucose uptake, mitochondrial gene expression, and vascular permeability to control adipose mass and function, providing a target for obesity therapy.

SUBMITTER: Lee KY

PROVIDER: S-EPMC3206000 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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The differential role of Hif1β/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation.

Lee Kevin Y KY Gesta Stephane S Boucher Jeremie J Wang Xiaohui L XL Kahn C Ronald CR

Cell metabolism 20111001 4

In obesity, adipocytes distant from vasculature become hypoxic and dysfunctional. This hypoxic response is mediated by hypoxia-inducible factors (Hif1α, Hif2α, and Hif3α) and their obligate partner, Hif1β (Arnt). We show that mice lacking Hif1β in fat (FH1βKO) are lean, exhibit reduced adipocyte size, and are protected from age- and diet-induced glucose intolerance. There is also reduced Vegf and vascular permeability in FH1βKO fat, but diet-induced inflammation and fibrosis is unchanged. Adipoc ...[more]

PMID: 21982709

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Project description:Hypoxia-inducible factor (HIF1?) plays an integral role in response to hypoxia, controlling dozens of target genes including aldolaseC (ALDC), an important enzyme in the glycolytic pathway. It also induces angiogenesis, allowing survival and proliferation of cancer cells. The aims of our study were to evaluate the expressions of HIF1? and ALDC in patients with endometrial cancer (EC) and define their association with disease outcome and to determine the existence of an association between HIF1? and ALDC proteins.This is a population-based retrospective cohort study using the gynaecological-oncology database. The authors identified all women with EC with adequate follow-up. Immunohistochemistry using antibodies to ALDC and HIF1? was performed on paraffin-embedded tissue from 279 patients. To test the association between ALDC /HIF1? protein using immunohistochemistry (IHC) (positive and negative) and the clinical parameters, Fisher's exact test was performed for categorical parameters and the logistic regression model was used for continuous ones. Pearson correlation was used to check the association of IHC between ALDC and HIF1?.Academic referral centre.Women with EC from 2000 to 2010 obtained from the gynaecological-oncology database.The disease outcome is defined by alive with no evidence of disease versus all other outcomes.ALDC and HIF1? were overexpressed in the vast majority of EC cases (78% and 76%, respectively). There was a strong positive association between HIF1? and ALDC (p=0.0017). There was a significant association between ALDC and depth of myometrial invasion (p=0.0438), and between HIF1? and tumour grade (p=0.0231) and tumour subtype (p=0.018). However, there was no association between neither ALDC nor HIF1? and disease status.ALDC and HIF1? play an important role in endometrial carcinogenesis. Their expression by the majority of EC makes inhibition of HIF1? a very attractive therapeutic option for treating patients with EC and we suggest that it will be prospectively validated in future studies.

Dataset Information

The differential role of Hif1?/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation.

Publications

The differential role of Hif1β/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation.

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