title: SOCS3 and SOCS6 are required for the risperidone-mediated inhibition of insulin and leptin signaling in neuroblastoma cells.
abstract: Antipsychotic drugs are regularly used for the treatment of many types of psychiatric disorders. The administration of second-generation antipsychotics is often associated with weight gain and the development of diabetes mellitus; however, the molecular mechanisms underlying the effects of these drugs remain poorly understood. Leptin and insulin play key roles in the regulation of energy balance and glucose homeostasis, and resistance to the actions of these hormones can occur with obesity and inflammation, resulting in the pathogenesis of obesity and type 2 diabetes. In this study, the effects of risperidone on the insulin-induced protein kinase B (PKB) phosphorylation and leptin-stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation were investigated in the human SH-SY5Y neuroblastoma cell line. The treatment of these cells with risperidone induced the activation of extracellular signal-related kinase (ERK) by cellular cyclic adenosine 3-monophosphate (cAMP)-dependent protein kinase (also known as protein kinase A; PKA) and the mechanisms involved include the induction of suppressor of cytokine signaling 3 (SOCS3) and suppressor of cytokine signaling 6 (SOCS6) expression. The risperidone-induced ERK activation induced an upregulation of SOCS3 and SOCS6 mRNA expression levels. Taken together, these results suggest that risperidone modulates SOCS3 and SOCS6 expression through adenylate cyclase-mediated ERK activation, which, in turn, leads to an inhibition of insulin-induced PKB phosphorylation and leptin-stimulated STAT3 phosphorylation. Eventually, these effects result in excessive body weight gain due to the inhibition of both the leptin and insulin signaling pathways.
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Longzhen
authors.initials: L
authors.lastname: Piao
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Gyeyeong
authors.initials: G
authors.lastname: Kong
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Robin
authors.initials: R
authors.lastname: Shrestha
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Quangdon
authors.initials: Q
authors.lastname: Tran
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
authors.affiliation: Department of Psychiatry, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
authors.forename: Jeong-Lan
authors.initials: JL
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Jongsun
authors.initials: J
authors.lastname: Park
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D020738:Leptin / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D018967:Risperidone / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; C106644:SOCS3 protein, human; C473085:SOCS6 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018967:Risperidone