Carrageenan Inhibits Insulin Signaling through GRB10-Mediated Decrease in Phospho(Tyr)-IRS1 and through Inflammation-Induced Increase in Phospho(Ser307)-IRS1.
Carrageenan Inhibits Insulin Signaling through GRB10-Mediated Decrease in Phospho(Tyr)-IRS1 and through Inflammation-Induced Increase in Phospho(Ser307)-IRS1.
Bhattacharyya S1, Feferman L2, Tobacman JK3.
1University of Illinois at Chicago, United States
2University of Illinois at Chicago and Jesse Brown VA Medical Center, United States.
3University of Illinois at Chicago and Jesse Brown VA Medical Center, United States
Abstract
Inflammation induced by exposure to the common food additive carrageenan leads to insulin resistance by increase in phospho(Ser307)IRS1 and subsequent decline in the insulin-stimulated increase in phospho(Ser473)AKT. Inhibition of carrageenan-induced inflammation reversed the increase in p(S307)IRS1, but did not completely reverse the carrageenan-induced decline in p(S473)AKT. To identify the additional mechanism responsible for the decrease in p(S473)AKT, studies were performed in human HepG2 cells and in C57BL/6J mice. Following carrageenan, expression of Growth Factor Receptor-Bound(GRB)10 protein, an adaptor protein that binds to the insulin receptor and inhibits insulin signaling, increased significantly. GRB10 silencing blocked the carrageenan-induced reduction of the insulin-stimulated increase in p(Tyr)IRS1 and partially reversed the decline in p(S473)AKT. The combination of GRB10 silencing with BCL10 silencing and the ROS-inhibitor Tempol completely reversed the decline in p(S473)AKT. After carrageenan, GRB10 promoter activity was enhanced, due to activation by GATA2. A direct correlation between p(S473)AKT and p(S401)GATA2 was evident, and inhibition of AKT phosphorylation by the PI3K inhibitor LY294002 blocked (S401)GATA2 phosphorylation and the increase in GRB10 expression. Studies indicated that carrageenan inhibited insulin signaling by two mechanisms: through the inflammation-mediated increase in p(S307)IRS1, a negative regulator of insulin signaling, and through a transcriptional mechanism leading to increase in GRB10 expression and GRB10-inhibition of p(Tyr)IRS1, a positive regulator of insulin signaling. These mechanisms converge to inhibit the insulin-induced increase in p(S473)AKT. They provide an internal feedback, mediated by p(S473)AKT, p(S401)GATA2, and nuclear GATA2, which links the opposing effects of serine and tyrosine phosphorylations of IRS1 and can modulate insulin responsiveness.
