title: IRS1Ser³⁰⁷ phosphorylation does not mediate mTORC1-induced insulin resistance.
abstract: Increased mammalian target of rapamycin complex 1 (mTORC1) activity has been suggested to play important roles in development of insulin resistance in obesity. mTORC1 hyperactivity also increases endoplasmic reticulum (ER) stress, which in turn contributes to development of insulin resistance and glucose intolerance. Increased IRS1 phosphorylation at Ser307 in vitro is correlated with mTORC1- and ER stress-induced insulin resistance. This phosphorylation site correlates strongly with impaired insulin receptor signaling in diabetic mice and humans. In contrast, evidence from knock-in mice suggests that phosphorylation of IRS1 at Ser307 is actually required to maintain insulin sensitivity. To study the involvement of IRS1(Ser307) phosphorylation in mTORC1-mediated glucose intolerance and insulin sensitivity in vivo, we investigated the effects of liver specific TSC1 depletion in IRS1(Ser307Ala) mice and controls. Our results demonstrate that blockade of IRS1(Ser307) phosphorylation in vivo does not prevent mTORC1-mediated glucose intolerance and insulin resistance.
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Hilde
authors: H
authors: Herrema
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Jaemin
authors: J
authors: Lee
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Yingjiang
authors: Y
authors: Zhou
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Kyle D
authors: KD
authors: Copps
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Morris F
authors: MF
authors: White
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: umut.ozcan@childrens.harvard.edu.
authors: Umut
authors: U
authors: Ozcan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D046912:Multiprotein Complexes; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D012694:Serine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Diabetes; ER stress; IRS1; mTORC1