TY - JOUR
T1 - Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity
AU - Lee, Yun Sok
AU - Kim, Jung Whan
AU - Osborne, Olivia
AU - Oh, Dayoung
AU - Sasik, Roman
AU - Schenk, Simon
AU - Chen, Ai
AU - Chung, Heekyung
AU - Murphy, Anne
AU - Watkins, Steven M.
AU - Quehenberger, Oswald
AU - Johnson, Randall S.
AU - Olefsky, Jerrold M.
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) grants DK-033651, DK-074868, DK-063491, and P01-DK054441. Y.S.L. was supported by a Mentor-Based Postdoctoral Fellowship Award from the American Diabetes Association. S.S. is supported by the National Institute of Aging and National Institute of Child Health and Human Development of the NIH under award numbers R01AG043120 and R24HD050837. R.S.J. is supported by a Principal Research Fellowship from the Wellcome Trust.
PY - 2014/6/5
Y1 - 2014/6/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.05.012
DO - 10.1016/j.cell.2014.05.012
M3 - Article
C2 - 24906151
AN - SCOPUS:84902075318
SN - 0092-8674
VL - 157
SP - 1339
EP - 1352
JO - Cell
JF - Cell
IS - 6
ER -