Role of FoxO1 in FFA-induced oxidative stress in adipocytes

Abstract

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. inflammatory cytokines; insulin resistance; fatty acids OBESITY IS ASSOCIATED WITH insulin resistance and an increased risk for diabetes and cardiovascular disease (16,18). The strong association between obesity and insulin resistance implicates the adipocyte as an important link in the pathophysiology of these diseases. Adipose tissue from obese individuals show activation of inflammatory pathways, with the elaboration of cytokines such as monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and 22) contributing to the systemic inflammation characteristic of obesity. Free fatty acids (FFA) are likely important mediators of this response, in part through the activation of PKC and IB kinase ␤, each of which can activate inflammatory pathways and also inhibit insulin signaling (14,33).In addition to having an important role in the activation of inflammatory pathways, fatty acids are also implicated in the activation of oxidative stress, not only by uncoupling oxidative phosphorylation and increasing the generation of oxygen species but also by impairing endogenous antioxidant defenses (31). In diabetes, the increased flux of FFA increases mitochondrial reactive oxygen species (ROS) production, which in turn interferes with insulin signaling (15). If lipid oversupply is causally linked to the inflammatory response and to the generation of oxidative stress, it is reasonable to expect that approaches that have antioxidant and anti-inflammatory effects on adipocytes should have a beneficial effect on insulin sensitivity.The FoxO (forkhead member of the class O) family of forkhead transcription factors comprises three functionally related ...

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

“…FFAs have been shown to increase ROS generation in 3T3-L1 adipocytes (44,45). We observed a similar phenomenon when cellular FFAs were increased by stimulating lipolysis.…”

“…7B) or other lipolytic agents. 3 Most impressively, the effect of isoproterenol was magnified 5-fold in the presence of compound C. Enhanced ROS production has been found previously in 3T3-L1 adipocytes incubated with exogenous saturated or unsaturated FFAs (45), an effect attributed to an up-regulation of NAD(P)H oxidase activity (44). Likewise, increased ROS production has been demonstrated in white adipose tissue of an obese insulin-resistant rodent, the KKAy mice (44).…”

Beneficial Effects of Grape Resveratrol on Serum Adiponectin and Inflammation: Clinical Trial in Patients with Stable Coronary Artery Disease

“…These results clearly illustrate thast GE-RSE dietary intervention leads to a drastic improvement in circulating biomarker levels and are consistent with previous findings showing that resveratrol mediates SIRT1/FOXO1 dependent upregulation of adiponectin and downregulation of PPARγ [32,33]. SIRT-1/FOXO1 is one the major signaling pathways activated by resveratrol.…”

Apelin Attenuates Oxidative Stress in Human Adipocytes

“…It is also known that mitochondrial oxidative stress triggered by ROS inhibits aconitase in the tricarboxylic acid cycle (TCA cycle) leading to increased biosynthesis of fatty acids (76,77). Moreover, ROS stimulates lipolysis by recruiting the hormone sensitive lipase to the lipid droplets (13,78), resulting in increased release of free fatty acids which, in turn, leads to increase of ROS generation and insulin resistance (79,80). We have previously shown that apelin suppresses adipogenesis and lipolysis (22).…”