title: Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state.
abstract: The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic β-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases β-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β-cell-specific Htr2b(-/-) (Htr2b βKO), Htr3a(-/-) (Htr3a knock-out [KO]), and β-cell-specific tryptophan hydroxylase 1 (Tph1)(-/-) (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO, and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state.
authors.affiliation: Graduate School of Medical Science and Engineering (K.K., C.-M.O., S.P., J.N., H.K.), Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea; Department of Biochemistry (M.O.-I., S.N.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Biochemistry (S.P.), Catholic Kwandong University College of Medicine, Gangneung, Gangwondo 210-701, Republic of Korea; Department of Biochemistry (J.N.), Yonsei University Wonju College of Medicine, Wonju, Gangwondo 220-701, Republic of Korea; Department of Genetics and Development (V.K.Y., G.K.), Columbia University Medical Center, New York, New York 10032; Department of Medicine (N.A.T., L.H.P.), The University of Chicago, Chicago, Illinois 60637; Departments of Medicine and Cell and Developmental Biology (M.W.R.), State University of New York Upstate Medical University, Syracuse, New York 13210; and Diabetes Center (M.S.G.), Hormone Research Institute and Department of Medicine, University of California San Francisco, San Francisco, California 94143.
authors.forename: Kyuho
authors.initials: K
authors.lastname: Kim
authors.forename: Chang-Myung
authors.initials: CM
authors.lastname: Oh
authors.forename: Mica
authors.initials: M
authors.lastname: Ohara-Imaizumi
authors.forename: Sangkyu
authors.initials: S
authors.lastname: Park
authors.forename: Jun
authors.initials: J
authors.lastname: Namkung
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Yadav
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Tamarina
authors.forename: Michael W
authors.initials: MW
authors.lastname: Roe
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
authors.forename: Hail
authors.initials: H
authors.lastname: Kim
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D018345:Mice, Knockout; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology*; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D011985:Receptors, Serotonin; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase