title: FoxO1 Plays an Important Role in Regulating β-Cell Compensation for Insulin Resistance in Male Mice.
abstract: β-Cell compensation is an essential mechanism by which β-cells increase insulin secretion for overcoming insulin resistance to maintain euglycemia in obesity. Failure of β-cells to compensate for insulin resistance contributes to insulin insufficiency and overt diabetes. To understand the mechanism of β-cell compensation, we characterized the role of forkhead box O1 (FoxO1) in β-cell compensation in mice under physiological and pathological conditions. FoxO1 is a key transcription factor that serves as a nutrient sensor for integrating insulin signaling to cell metabolism, growth, and proliferation. We showed that FoxO1 improved β-cell compensation via 3 distinct mechanisms by increasing β-cell mass, enhancing β-cell glucose sensing, and augmenting β-cell antioxidative function. These effects accounted for increased glucose-stimulated insulin secretion and enhanced glucose tolerance in β-cell-specific FoxO1-transgenic mice. When fed a high-fat diet, β-cell-specific FoxO1-transgenic mice were protected from developing fat-induced glucose disorder. This effect was attributable to increased β-cell mass and function. Furthermore, we showed that FoxO1 activity was up-regulated in islets, correlating with the induction of physiological β-cell compensation in high-fat-induced obese C57BL/6J mice. These data characterize FoxO1 as a pivotal factor for orchestrating physiological adaptation of β-cell mass and function to overnutrition and obesity.
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Sojin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Virtu
authors.initials: V
authors.lastname: Calabuig-Navarro
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamauchi
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Rennian
authors.initials: R
authors.lastname: Wang
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Alvarez-Perez
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: George
authors.initials: G
authors.lastname: Gittes
authors.affiliation: Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.
authors.forename: H Henry
authors.initials: HH
authors.lastname: Dong
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D059305:Diet, High-Fat; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009929:Organ Size; D010179:Pancreas / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; C495682:Slc2a2 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein