title: Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats: involvement of the INSIG/SREBP pathway.
abstract: Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile.
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China; Department of Pharmacy, Jining First People's Hospital, Jining, China.
authors.forename: Ruili
authors.initials: R
authors.lastname: Dang
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China; Department of Pharmacy, Jining First People's Hospital, Jining, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Hualin
authors.initials: H
authors.lastname: Cai
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China. Electronic address: lihuande1953@126.com.
authors.forename: Huande
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Guo
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China; School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Wenye
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001835:Body Weight; D003024:Clozapine / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004435:Eating; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat; D008297:Male; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000009:adverse effects / Q000494:pharmacology*; D014808:Vitamin D Deficiency / Q000378:metabolism* / Q000473:pathology
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine; D018967:Risperidone
keywords: Atypical antipsychotics; Insulin-induced genes; Lipid; Sterol regulatory element-binding proteins; Vitamin D deficiency