{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:42:08Z","timestamp":1792273328456,"version":"4.4.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T00:00:00Z","timestamp":1639440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of\u00a0Hunan Province","doi-asserted-by":"publisher","award":["2021JJ30922"],"award-info":[{"award-number":["2021JJ30922"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017695","name":"Health Commission of Hunan Province","doi-asserted-by":"publisher","award":["202113010595"],"award-info":[{"award-number":["202113010595"]}],"id":[{"id":"10.13039\/100017695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007452","name":"Wu Jieping Medical Foundation","doi-asserted-by":"publisher","award":["320.6750.2020-04-2"],"award-info":[{"award-number":["320.6750.2020-04-2"]}],"id":[{"id":"10.13039\/100007452","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012476","name":"Fundamental Research Funds for Central Universities of the Central South University","doi-asserted-by":"publisher","award":["2020zzts884, 2021zzts1073, 2019zzts1049"],"award-info":[{"award-number":["2020zzts884, 2021zzts1073, 2019zzts1049"]}],"id":[{"id":"10.13039\/501100012476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Newly emerging evidence has implicated that progesterone receptor component 1 (PGRMC1) plays a novel role not only in the lipid disturbance induced by atypical antipsychotic drugs (AAPD) but also in the deterioration of glucose homoeostasis induced by clozapine (CLZ) treatment. The present study aimed to investigate the role of PGRMC1 signaling on hepatic gluconeogenesis and glycogenesis in male rats following CLZ treatment (20 mg\/kg daily for 4 weeks). Recombinant adeno-associated viruses (AAV) were constructed for the knockdown or overexpression of hepatic PGRMC1. Meanwhile, AG205, the specific inhibitor of PGRMC1 was also used for functional validation of PGRMC1. Hepatic protein expressions were measured by western blotting. Meanwhile, plasma glucose, insulin and glucagon, HbA1c and hepatic glycogen were also determined by assay kits. Additionally, concentrations of progesterone (PROG) in plasma, liver and adrenal gland were measured by a liquid chromatography-tandem mass spectrometry (LC-MS\/MS) method. Our study demonstrated that CLZ promoted the process of gluconeogenesis and repressed glycogenesis, respectively mediated by PI3K-Akt-FOXO1 and GSK3\u03b2 signaling <jats:italic>via<\/jats:italic> inhibition of PGRMC1-EGFR\/GLP1R in rat liver, along with an increase in fasting blood glucose, HbA1c levels and a decrease in insulin and hepatic glycogen levels. Furthermore, through PGRMC1-EGFR\/GLP1R-PI3K-Akt pathway, knockdown or inhibition (by AG205) of PGRMC1 mimics, whereas its overexpression moderately alleviates CLZ-induced glucose disturbances. Potentially, the PGRMC1 target may be regarded as a novel therapeutic strategy for AAPD-induced hepatic glucose metabolism disorder.<\/jats:p>","DOI":"10.3389\/fendo.2021.727371","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T09:18:20Z","timestamp":1639473500000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Clozapine Induced Disturbances in Hepatic Glucose Metabolism: The Potential Role of PGRMC1 Signaling"],"prefix":"10.3389","volume":"12","author":[{"given":"Ting","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"BiKui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiangXin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CuiRong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ShuangYang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HuaLin","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2019.00803","article-title":"Changes in Body Fat and Related Biochemical Parameters Associated With Atypical Antipsychotic Drug Treatment in Schizophrenia Patients With or Without Metabolic Syndrome","volume":"10","author":"Kornetova","year":"2019","journal-title":"Front Psychiatry"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2012.08.015","article-title":"Insight Into Mechanism of In Vitro Insulin Secretion Increase Induced by Antipsychotic Clozapine: Role of FOXA1 and Mitochondrial Citrate Carrier","volume":"23","author":"Menga","year":"2013","journal-title":"Eur Neuropsychopharmacol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301209","article-title":"Acute Effects of Atypical Antipsychotics on Whole-Body Insulin Resistance in Rats: Implications for Adverse Metabolic Effects","volume":"32","author":"Houseknecht","year":"2007","journal-title":"Neuropsychopharmacology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200464070-00003","article-title":"Adverse Metabolic Effects Associated With Atypical Antipsychotics: Literature Review and Clinical Implications","volume":"64","author":"Melkersson","year":"2004","journal-title":"Drugs"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/1099-081x","article-title":"Pharmacokinetics and Tissue Distribution of Olanzapine in Rats","volume":"20","author":"Aravagiri","year":"1999","journal-title":"Biopharm Drug Dispos"},{"key":"B6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1159\/000100981","article-title":"Clozapine-Induced Alteration of Glucose Homeostasis in the Rat: The Contribution of Hypothalamic-Pituitary-Adrenal Axis Activation","volume":"85","author":"Tulipano","year":"2007","journal-title":"Neuroendocrinology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-006-0446-6","article-title":"The Atypical Antipsychotic Clozapine Impairs Insulin Secretion by Inhibiting Glucose Metabolism and Distal Steps in Rat Pancreatic Islets","volume":"49","author":"Sasaki","year":"2006","journal-title":"Diabetologia"},{"key":"B8","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.schres.2009.07.011","article-title":"Clozapine and Quetiapine Acutely Reduce Glucagon-Like Peptide-1 Production and Increase Glucagon Release in Obese Rats: Implications for Glucose Metabolism and Food Choice Behaviour","volume":"115","author":"Smith","year":"2009","journal-title":"Schizophr Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2762","DOI":"10.1038\/s41598-017-02884-w","article-title":"Time-Dependent Changes and Potential Mechanisms of Glucose-Lipid Metabolic Disorders Associated With Chronic Clozapine or Olanzapine Treatment in Rats","volume":"7","author":"Liu","year":"2017","journal-title":"Sci Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-014-3608-0","article-title":"The Activation of the Akt\/PKB Signalling Pathway in the Brains of Clozapine-Exposed Rats is Linked to Hyperinsulinemia and Not a Direct Drug Effect","volume":"231","author":"Smith","year":"2014","journal-title":"Psychopharmacology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.18314\/jnb.v4i2.1081","article-title":"Insulin Receptor Levels Regulated by the Receptor- Associated Protein Progesterone Receptor Membrane Component 1 (PGRMC1)","volume":"4","author":"Craven","year":"2018","journal-title":"J Nutr Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2337\/db10-1270","article-title":"Global Gene Expression Profiles of Subcutaneous Adipose and Muscle From Glucose-Tolerant, Insulin-Sensitive, and Insulin-Resistant Individuals Matched for BMI","volume":"60","author":"Elbein","year":"2011","journal-title":"Diabetes"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M114.040196","article-title":"Progesterone Receptor Membrane Component 1 Is a Functional Part of the Glucagon-Like Peptide-1 (GLP-1) Receptor Complex in Pancreatic \u03b2 Cells","volume":"13","author":"Zhang","year":"2014","journal-title":"Mol Cell Proteomics MCP"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1124\/mol.117.110510","article-title":"Insulin Receptor Plasma Membrane Levels Increased by the Progesterone Receptor Membrane Component 1","volume":"94","author":"Hampton","year":"2018","journal-title":"Mol Pharmacol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e661","DOI":"10.1038\/tp.2015.161","article-title":"A Potential Mechanism Underlying Atypical Antipsychotics-Induced Lipid Disturbances","volume":"5","author":"Cai","year":"2015","journal-title":"Trans Psychiatry"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e218","DOI":"10.1038\/emm.2015.122","article-title":"Regulation of Glucose Metabolism From a Liver-Centric Perspective","volume":"48","author":"Han","year":"2016","journal-title":"Exp Mol Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C110.175851","article-title":"Foxos Function Synergistically to Promote Glucose Production","volume":"285","author":"Haeusler","year":"2010","journal-title":"J Biol Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/378785a0","article-title":"Inhibition of Glycogen Synthase Kinase-3 by Insulin Mediated by Protein Kinase B","volume":"378","author":"Cross","year":"1995","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11030","article-title":"Haem-Dependent Dimerization of PGRMC1\/Sigma-2 Receptor Facilitates Cancer Proliferation and Chemoresistance","volume":"7","author":"Kabe","year":"2016","journal-title":"Nat Commun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2017.03.013","article-title":"CB-1R and GLP-1R Gene Expressions and Oxidative Stress in the Liver of Diabetic Rats Treated With Sitagliptin","volume":"69","author":"Coskun","year":"2017","journal-title":"Pharmacol Rep PR"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-007-0721-1","article-title":"Collagen I Induction by High Glucose Levels is Mediated by Epidermal Growth Factor Receptor and Phosphoinositide 3-Kinase\/Akt Signalling in Mesangial Cells","volume":"50","author":"Wu","year":"2007","journal-title":"Diabetologia"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/s0968-0004(01)01958-2","article-title":"Ten Years of Protein Kinase B Signalling: A Hard Akt to Follow","volume":"26","author":"Brazil","year":"2001","journal-title":"Trends Biochem Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(04)00082-1","article-title":"The Effects of Clozapine on the GSK-3-Mediated Signaling Pathway","volume":"560","author":"Kang","year":"2004","journal-title":"FEBS Lett"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.612083","article-title":"A Potential Mechanism Underlying the Therapeutic Effects of Progesterone and Allopregnanolone on Ketamine-Induced Cognitive Deficits","volume":"12","author":"Cao","year":"2021","journal-title":"Front Pharmacol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-019-01956-2","article-title":"Quantitative Monitoring of a Panel of Stress-Induced Biomarkers in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry: An Application in a Comparative Study Between Depressive Patients and Healthy Subjects","volume":"411","author":"Cai","year":"2019","journal-title":"Anal Bioanal Chem"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1996.0726u.x","article-title":"Purification and Partial Sequencing of High-Affinity Progesterone-Binding Site(s) From Porcine Liver Membranes","volume":"239","author":"Meyer","year":"1996","journal-title":"Eur J Biochem"},{"key":"B27","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1146\/annurev.ph.54.030192.004321","article-title":"Molecular Physiology of the Regulation of Hepatic Gluconeogenesis and Glycolysis","volume":"54","author":"Pilkis","year":"1992","journal-title":"Annu Rev Physiol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1146\/annurev.nutr.19.1.379","article-title":"Regulation of Glucose Production by the Liver","volume":"19","author":"Nordlie","year":"1999","journal-title":"Annu Rev Nutr"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.68.040104.124723","article-title":"From Mice to Men: Insights Into the Insulin Resistance Syndromes","volume":"68","author":"Biddinger","year":"2006","journal-title":"Annu Rev Physiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2008.09.006","article-title":"PGRMC1 (Progesterone Receptor Membrane Component 1): A Targetable Protein With Multiple Functions in Steroid Signaling, P450 Activation and Drug Binding","volume":"121","author":"Rohe","year":"2009","journal-title":"Pharmacol Ther"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2015.10.017","article-title":"The Sigma-2 Receptor and Progesterone Receptor Membrane Component 1 are Different Binding Sites Derived From Independent Genes","volume":"2","author":"Chu","year":"2015","journal-title":"EBioMedicine"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/17.12.2609","article-title":"Isolation and Characterization of a Novel Gene Induced by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin in Rat Liver","volume":"17","author":"Selmin","year":"1996","journal-title":"Carcinogenesis"},{"key":"B33","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/nature13478","article-title":"The Role of Hepatic Lipids in Hepatic Insulin Resistance and Type 2 Diabetes","volume":"510","author":"Perry","year":"2014","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1042\/CS20130670","article-title":"Gdcl3 Reduces Hyperglycaemia Through Akt\/Foxo1-Induced Suppression of Hepatic Gluconeogenesis in Type 2 Diabetic Mice","volume":"127","author":"Wang","year":"2014","journal-title":"Clin Sci (London Engl 1979)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3370","article-title":"Targeting Forkhead Box O1 From the Concept to Metabolic Diseases: Lessons From Mouse Models","volume":"14","author":"Cheng","year":"2011","journal-title":"Antioxidants Redox Signal"},{"key":"B36","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.nutres.2019.05.008","article-title":"Glutamine Administration Promotes Hepatic Glucose Homeostasis Through Regulating the PI3K\/Akt Pathway in High-Fat Diet-Induced Obese Mice With Limb Ischemia","volume":"68","author":"Pitaloka","year":"2019","journal-title":"Nutr Res (New York NY)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-007-0836-4","article-title":"Progesterone Impairs Cell Respiration and Suppresses a Compensatory Increase in Glucose Transport in Isolated Rat Skeletal Muscle: A Non-Genomic Mechanism Contributing to Metabolic Adaptation to Late Pregnancy","volume":"50","author":"Gras","year":"2007","journal-title":"Diabetologia"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0317-20.2020","article-title":"Proceedings From the Fourth International Symposium on \u03c2-2 Receptors: Role in Health and Disease","volume":"7","author":"Izzo","year":"2020","journal-title":"eNeuro"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/sj.npp.1300015","article-title":"Olanzapine and Clozapine Increase the Gabaergic Neuroactive Steroid Allopregnanolone in Rodents","volume":"28","author":"Marx","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.116979","article-title":"Effects of Progesterone on Glucose Uptake in Neurons of Alzheimer\u2019s Disease Animals and Cell Models","volume":"238","author":"Wu","year":"2019","journal-title":"Life Sci"},{"key":"B41","article-title":"Effect of Ovarian Hormones and Estrous Cycle on Stimulation of the Hypothalamo-Pituitary-Adrenal Axis by Cocaine","volume":"297","author":"Walker","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1210\/endo-84-1-171","article-title":"Stimulation of Progesterone Release and Estrous Behavior by ACTH in Ovariectomized Rodents","volume":"84","author":"Feder","year":"1969","journal-title":"Endocrinology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.euroneuro.2007.04.005","article-title":"The Influence of Clozapine Treatment and Other Antipsychotics on the 18 Kda Translocator Protein, Formerly Named the Peripheral-Type Benzodiazepine Receptor, and Steroid Production","volume":"18","author":"Danovich","year":"2008","journal-title":"Eur Neuropsychopharmacol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e1130","DOI":"10.1038\/tp.2017.94","article-title":"Therapeutic Efficacy of Atypical Antipsychotic Drugs by Targeting Multiple Stress-Related Metabolic Pathways","volume":"7","author":"Cai","year":"2017","journal-title":"Trans Psychiatry"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2165\/00023210-200519001-00001","article-title":"Second-Generation (Atypical) Antipsychotics and Metabolic Effects: A Comprehensive Literature Review","volume":"19","author":"Newcomer","year":"2005","journal-title":"CNS Drugs"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2013.08.034","article-title":"Investigation of the Metabolic Effects of Chronic Clozapine Treatment on CCK-1 Receptor Deficient Otsuka Long Evans Tokushima Fatty (OLETF) Rats","volume":"718","author":"Heged\u0171s","year":"2013","journal-title":"Eur J Pharmacol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2007.09.012","article-title":"Chronic Clozapine Treatment in Female Rats Does Not Induce Weight Gain or Metabolic Abnormalities But Enhances Adiposity: Implications for Animal Models of Antipsychotic-Induced Weight Gain","volume":"32","author":"Cooper","year":"2008","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(93)90084-7","article-title":"Effects of Long-Term Administration of Clozapine on Body Weight and Food Intake in Rats","volume":"45","author":"Baptista","year":"1993","journal-title":"Pharmacol Biochem Behav"},{"key":"B49","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/oby.2006.6","article-title":"Hormonal and Metabolic Effects of Olanzapine and Clozapine Related to Body Weight in Rodents","volume":"14","author":"Albaugh","year":"2006","journal-title":"Obesity"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-1152-3","article-title":"Atypical Antipsychotic Drugs Induce Derangements in Glucose Homeostasis by Acutely Increasing Glucagon Secretion and Hepatic Glucose Output in the Rat","volume":"51","author":"Smith","year":"2008","journal-title":"Diabetologia"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2008.06.105","article-title":"The Antipsychotics Clozapine and Olanzapine Increase Plasma Glucose and Corticosterone Levels in Rats: Comparison With Aripiprazole, Ziprasidone, Bifeprunox and F15063","volume":"592","author":"Assi\u00e9","year":"2008","journal-title":"Eur J Pharmacol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/s42003-020-01202-x","article-title":"Progesterone Receptor Membrane Associated Component 1 Enhances Obesity Progression in Mice by Facilitating Lipid Accumulation in Adipocytes","volume":"3","author":"Furuhata","year":"2020","journal-title":"Commun Biol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.727371\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T09:18:26Z","timestamp":1639473506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.727371\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,14]]},"references-count":52,"alternative-id":["10.3389\/fendo.2021.727371"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.727371","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,14]]},"article-number":"727371"}}