title: Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1.
abstract: Inflammation induced by exposure to the common food additive carrageenan leads to insulin resistance by increase in Ser(P)(307)-insulin receptor substrate 1 (IRS1) and subsequent decline in the insulin-stimulated increase in Ser(P)(473)-AKT. Inhibition of carrageenan-induced inflammation reversed the increase in Ser(P)(307)-IRS1 but did not completely reverse the carrageenan-induced decline in Ser(P)(473)-AKT. To identify the additional mechanism responsible for the decrease in Ser(P)(473)-AKT, studies were performed in human HepG2 cells and in C57BL/6J mice. Following carrageenan, expression of GRB10 (growth factor receptor-bound 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 Tyr(P)-IRS1 and partially reversed the decline in Ser(P)(473)-AKT. The combination of GRB10 silencing with BCL10 silencing and the reactive oxygen species inhibitor Tempol completely reversed the decline in Ser(P)(473)-AKT. After carrageenan, GRB10 promoter activity was enhanced because of activation by GATA2. A direct correlation between Ser(P)(473)-AKT and Ser(P)(401)-GATA2 was evident, and inhibition of AKT phosphorylation by the PI3K inhibitor LY294002 blocked Ser(401)-GATA2 phosphorylation and the increase in GRB10 expression. Studies indicated that carrageenan inhibited insulin signaling by two mechanisms: through the inflammation-mediated increase in Ser(P)(307)-IRS1, a negative regulator of insulin signaling, and through a transcriptional mechanism leading to increase in GRB10 expression and GRB10-inhibition of Tyr(P)-IRS1, a positive regulator of insulin signaling. These mechanisms converge to inhibit the insulin-induced increase in Ser(P)(473)-AKT. They provide internal feedback, mediated by Ser(P)(473)-AKT, Ser(P)(401)-GATA2, and nuclear GATA2, which links the opposing effects of serine and tyrosine phosphorylations of IRS1 and can modulate insulin responsiveness.
authors.affiliation: From the Department of Medicine, University of Illinois at Chicago and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: From the Department of Medicine, University of Illinois at Chicago and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
authors.forename: Leo
authors.initials: L
authors.lastname: Feferman
authors.affiliation: From the Department of Medicine, University of Illinois at Chicago and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612 jkt@uic.edu.
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Tobacman
mesh_terms: D000818:Animals; D002351:Carrageenan / Q000633:toxicity*; D050989:GATA2 Transcription Factor / Q000378:metabolism; D051383:GRB10 Adaptor Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000737:chemistry / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015233:Models, Statistical; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C096358:GRB10 protein, human; C494712:Gata2 protein, mouse; C495959:Grb10 protein, mouse; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D034741:RNA, Small Interfering; D051383:GRB10 Adaptor Protein; D014443:Tyrosine; D012694:Serine; D002351:Carrageenan; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt PKB; Carrageenan; GATA Transcription Factor; GRB10; Inflammation; Insulin Receptor Substrate 1 (IRS-1); Insulin Resistance