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

Jonathan Jun, Ronald Devera, Dileep Unnikrishnan, Mi-Kyung Shin, Shannon Bevans-Fonti, Qiaoling Yao, Aman Rathore, Haris Younas, Nils Halberg, Philipp E. Scherer, Vsevolod Polotsky

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalJournal of Molecular Medicine
DOIs
StateAccepted/In press - Oct 14 2016

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Keywords

  • Brown adipose
  • HIF
  • Hypoxia
  • Obesity
  • Thermogenesis

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Jun, J., Devera, R., Unnikrishnan, D., Shin, M-K., Bevans-Fonti, S., Yao, Q., Rathore, A., Younas, H., Halberg, N., Scherer, P. E., & Polotsky, V. (Accepted/In press). Adipose HIF-1α causes obesity by suppressing brown adipose tissue thermogenesis. Journal of Molecular Medicine, 1-11. https://doi.org/10.1007/s00109-016-1480-6