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Adipose HIF-1α causes obesity by suppressing brown adipose tissue thermogenesis

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Abstract

Hypoxia-inducible factor-1α (HIF-1α) in adipose tissue is known to promote obesity. We hypothesized that HIF-1α interferes with brown fat thermogenesis, thus decreasing energy expenditure. To test this hypothesis, we compared transgenic mice constitutively expressing HIF-1α in adipose tissues (HIF-1α++) at usual temperature (22 °C), where brown fat is somewhat active, or at thermoneutrality (30 °C), where brown fat is minimally active. HIF-1α++ mice or control litter mates were separated into room temperature (22 °C) or thermoneutrality (30 °C) groups. We assessed weight gain, food intake, calorimetry, activity, and oxygen consumption and transcriptional changes in isolated white and brown adipocytes. At 22 °C, HIF-1α++ mice exhibited accelerated weight gain, cold and glucose intolerance, hyperglycemia, and decreased energy expenditure without changes in food intake or activity. These changes were absent or minimal at thermoneutrality. In brown adipocytes of HIF-1α++ mice, oxygen consumption decreased ~50 % in association with reduced mitochondrial content, uncoupling protein 2, and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α). In conclusion, adipose HIF-1α overexpression inhibits thermogenesis and cellular respiration in brown adipose tissue, promoting obesity in the setting of reduced ambient temperature.

Key message

  • Constitutive HIF-1α activation in adipose tissue promotes weight gain in mice.

  • The weight gain is associated with reduced brown adipose tissue function and oxygen consumption.

  • Reduced oxygen consumption may be mediated by reductions in mitochondria.

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins, University School of Medicine, 5501 Hopkins Bayview Circle Room 4A30A, Baltimore, MD, 21224, USA

    Jonathan C. Jun, Ronald Devera, Dileep Unnikrishnan, Mi-Kyung Shin, Shannon Bevans-Fonti, Qiaoling Yao, Aman Rathore, Haris Younas & Vsevolod Y. Polotsky

  2. Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Nils Halberg & Philipp E. Scherer

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  1. Jonathan C. Jun
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Correspondence to Jonathan C. Jun.

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Funding

J. Jun was funded by National Institutes of Health 1K08-HL109475. V. Polotsky was funded by National Institutes of Health R01-HL080105, R01-HL128970, R01-HL133100, and P50-ES018176 and American Sleep Foundation 133-BS-15. P. Scherer was funded by National Institutes of Health R01-DK55758, P01-DK088761, and R01-DK099110.

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Jun, J.C., Devera, R., Unnikrishnan, D. et al. Adipose HIF-1α causes obesity by suppressing brown adipose tissue thermogenesis. J Mol Med 95, 287–297 (2017). https://doi.org/10.1007/s00109-016-1480-6

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