Cell. 2014 Jun 5;157(6):1339-52. doi: 10.1016/j.cell.2014.05.012.

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

Lee YS¹, Kim JW², Osborne O¹, Oh DY¹, Sasik R¹, Schenk S³, Chen A¹, Chung H¹, Murphy A⁴, Watkins SM⁵, Quehenberger O¹, Johnson RS⁶, Olefsky JM⁷.

Author information

1: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
2: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
3: Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
4: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
5: Lipomics Technologies, Inc., West Sacramento, CA 95691, USA.
6: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, 171 77, Sweden; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK. Electronic address: rsj33@cam.ac.uk.
7: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jolefsky@ucsd.edu.

Abstract

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.