title: Inhibition of the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 by AICAR.
abstract: AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. However, the mechanism by which AMPK regulates insulin signaling remains unclear. Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling. Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. Taken together, these findings provide evidence that AMPK plays a crucial role in improving of type 2 diabetes.
authors.affiliation: Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Shibata
authors.forename: Akira
authors.initials: A
authors.lastname: Takaguri
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ichihara
authors.forename: Kumi
authors.initials: K
authors.lastname: Satoh
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism*; D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000209:etiology; D054637:Dual-Specificity Phosphatases / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; D000620:Aminoimidazole Carboxamide; D012694:Serine; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; C104821:DUSP9 protein, human; D054637:Dual-Specificity Phosphatases; C031143:AICA ribonucleotide