Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity

Yun Sok Lee, Jung Whan Kim, Olivia Osborne, Dayoung Oh, Roman Sasik, Simon Schenk, Ai Chen, Heekyung Chung, Anne Murphy, Steven M. Watkins, Oswald Quehenberger, Randall S. Johnson, Jerrold M. Olefsky

Research output: Contribution to journalArticlepeer-review

232 Scopus citations


Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.

Original languageEnglish (US)
Pages (from-to)1339-1352
Number of pages14
Issue number6
StatePublished - Jun 5 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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