title: 4-Hydroxyisoleucine attenuates the inflammation-mediated insulin resistance by the activation of AMPK and suppression of SOCS-3 coimmunoprecipitation with both the IR-β subunit as well as IRS-1.
abstract: It is known that 4-hydroxyisoleucine (4-HIL) from seeds of Trigonella foenum-graecum has beneficial effects on low-grade inflammation; therefore, the insulin signaling as well as the anti-inflammatory effects of 4-HIL in TNF-α-induced insulin resistance in C2C12 myotubes was studied with an aim to dissect out the mechanism(s) of the inflammation-mediated insulin resistance. TNF-α suppressed insulin-stimulated glucose transport rate and increased Ser-307 phosphorylation of insulin receptor substrate-1 (IRS-1). However, the treatment of 4-hydroxyisoleucine enhanced insulin-stimulated glucose transport rate via the activation of AMP-activated protein kinase (AMPK) in a dose-dependent manner. 4-HIL also increases the tyrosine phosphorylation of both IR-β and IRS-1. Moreover, coimmunoprecipitation (Co-IP) of insulin receptor-β (IR-β) subunit with IRS-1 was found to be increased by 4-hydroxyisoleucine. Concentration of SOCS-3 protein and coimmunoprecipitation of SOCS-3 protein with both the IR-β subunit as well as IRS-1 was found to be decreased by 4-HIL. We conclude that the 4-hydroxyisoleucine reverses the insulin resistance by the activation of AMPK and suppression of SOCS-3 coimmunoprecipitation with both the IR-β subunit as well as IRS-1.
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226021, India.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226021, India.
authors.forename: Nayab
authors.initials: N
authors.lastname: Ishrat
authors.affiliation: Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226021, India.
authors.forename: Pragya
authors.initials: P
authors.lastname: Yadav
authors.affiliation: Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226021, India.
authors.forename: Rohit
authors.initials: R
authors.lastname: Singh
authors.affiliation: Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226021, India.
authors.forename: Tadigoppula
authors.initials: T
authors.lastname: Narender
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226021, India. arvind_srivastava@cdri.res.in.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D047468:Immunoprecipitation; D007249:Inflammation / Q000517:prevention & control*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D010766:Phosphorylation; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: C104672:4-hydroxyisoleucine; D000730:Androstadienes; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C495693:Slc2a4 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D014409:Tumor Necrosis Factor-alpha; D007532:Isoleucine; D003847:Deoxyglucose; D000263:Adenylate Kinase; D000077191:Wortmannin
keywords: 4-HIL; C2C12 myotubes; Glucose uptake; Insulin resistance; TNF-α; Trigonella foenum-graecum