Role of FoxO1 in FFA-induced oxidative stress in adipocytes

Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E159-64. doi: 10.1152/ajpendo.00629.2006. Epub 2007 Mar 20.


Reactive oxygen species (ROS) production has recently been established as an essential contributor in the pathogenesis of obesity-associated insulin resistance. The FoxO1 pathway plays a role not only in nutrient sensing but also in regulating ROS production. We exposed adipocytes to free fatty acids (FFA) and demonstrated that FoxO1 protein levels decrease in a dose-dependent manner. The FoxO1 downregulation correlated with an increase in the production of ROS and a proinflammatory adipokine pattern characterized by a decrease in adiponectin and an increase in IL-6, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1 mRNA expression levels. Similarly, a decrease in FoxO1 protein levels was seen in adipocytes of db/db mice compared with controls. Treatment with the sirtuin agonist resveratrol, which translocates FoxO1 to the nucleus, increased FoxO1 protein levels in adipocytes exposed to FFA. This correlated with a decrease in the generation of ROS and a partial reversal of the proinflammatory adipokine pattern. Together these results indicate that the insulin-resistant adipocyte produced by the exposure to a high concentration of fatty acids is characterized by decreased levels of FoxO1. These data also suggest that modulation of the Sirt1/FoxO1 pathway is a potentially useful therapeutic target for the obesity-induced dysfunctional adipocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects*
  • Adipocytes / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Nucleus / metabolism
  • Diabetes Mellitus / metabolism
  • Fatty Acids, Nonesterified / pharmacology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / physiology*
  • Inflammation Mediators / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Resveratrol
  • Stilbenes / pharmacology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Fatty Acids, Nonesterified
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Inflammation Mediators
  • Reactive Oxygen Species
  • Stilbenes
  • Resveratrol