Journal of Biological Chemistry
Volume 285, Issue 43, 22 October 2010, Pages 32869-32877
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Metabolism
Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice*,

https://doi.org/10.1074/jbc.M110.135509Get rights and content
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Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1α (hypoxia-inducible factor 1α), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1α in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1α developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared with their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial biogenesis and reduced expression of key thermogenic genes. In the transgenic mice, angiogenesis in BAT was decreased but was little affected in white adipose tissue. These findings support an indispensable role of HIF1α in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue.

Hypoxia
Insulin resistance
Metabolic diseases
Mitochondria
Obesity
Adipose Tissue Biology
Brown Adipose Tissue
Energy Expenditure and Obesity
Thermogenesis

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*

This work was supported by Research Grants Council of Hong Kong General Research Fund Grant HKU 7645/06M and Collaborative Research Fund Grant HKU 2/07C, Natural Science Foundation of China Grant 30600300, and an Outstanding Young Researcher Award from the University of Hong Kong (to A. X.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S8.

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Supported in part by an HKU small project grant.