title: Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes.
abstract: Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for insulin to control transcription. Despite this, little is known about how insulin regulates FOXO1 and how FOXO1 may contribute to insulin resistance in adipocytes, which are the most critical cell type in the development of insulin resistance. We report a detailed mechanistic analysis of insulin control of FOXO1 in human adipocytes obtained from non-diabetic subjects and from patients with T2D. We show that FOXO1 is mainly phosphorylated through mTORC2-mediated phosphorylation of protein kinase B at Ser(473) and that this mechanism is unperturbed in T2D. We also demonstrate a cross-talk from the MAPK branch of insulin signaling to stimulate phosphorylation of FOXO1. The cellular abundance and consequently activity of FOXO1 are halved in T2D. Interestingly, inhibition of mTORC1 with rapamycin reduces the abundance of FOXO1 to the levels in T2D. This suggests that the reduction of the concentration of FOXO1 is a consequence of attenuation of mTORC1, which defines much of the diabetic state in human adipocytes. We integrate insulin control of FOXO1 in a network-wide mathematical model of insulin signaling dynamics based on compatible data from human adipocytes. The diabetic state is network-wide explained by attenuation of an mTORC1-to-insulin receptor substrate-1 (IRS1) feedback and reduced abundances of insulin receptor, GLUT4, AS160, ribosomal protein S6, and FOXO1. The model demonstrates that attenuation of the mTORC1-to-IRS1 feedback is a major mechanism of insulin resistance in the diabetic state.
authors.affiliation: From the Departments of Clinical and Experimental Medicine and.
authors.forename: Meenu Rohini
authors.initials: MR
authors.lastname: Rajan
authors.affiliation: Biomedical Engineering, Linköping University, SE58185 Linköping, Sweden and Cardiovascular and Metabolic Diseases, Innovative Medicines, and Drug Metabolism and Pharmacokinetics, AstraZeneca Research and Development, 43150 Gothenburg, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Nyman
authors.affiliation: From the Departments of Clinical and Experimental Medicine and.
authors.forename: Preben
authors.initials: P
authors.lastname: Kjølhede
authors.affiliation: From the Departments of Clinical and Experimental Medicine and Biomedical Engineering, Linköping University, SE58185 Linköping, Sweden and.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cedersund
authors.affiliation: From the Departments of Clinical and Experimental Medicine and peter.stralfors@liu.se.
authors.forename: Peter
authors.identifier: 0000-0002-1196-1806
authors.initials: P
authors.lastname: Strålfors
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D046912:Multiprotein Complexes; C495692:SLC2A4 protein, human; C518767:TBC1D4 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: adipocyte; human; insulin resistance; insulin signaling; mammalian target of rapamycin (mTOR); mathematical modeling; protein phosphorylation; ribosome biogenesis; transcription factor; type 2 diabetes