title: Clozapine modifies the differentiation program of human adipocytes inducing browning.
abstract: Administration of second-generation antipsychotic drugs (SGAs) often leads to weight gain and consequent cardio-metabolic side effects. We observed that clozapine but not six other antipsychotic drugs reprogrammed the gene expression pattern of differentiating human adipocytes ex vivo, leading to an elevated expression of the browning marker gene UCP1, more and smaller lipid droplets and more mitochondrial DNA than in the untreated white adipocytes. Laser scanning cytometry showed that up to 40% of the differentiating single primary and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes had the characteristic morphological features of browning cells. Furthermore, clozapine significantly upregulated ELOVL3, CIDEA, CYC1, PGC1A and TBX1 genes but not ZIC1 suggesting induction of the beige-like and not the classical brown phenotype. When we tested whether browning induced by clozapine can be explained by its known pharmacological effect of antagonizing serotonin (5HT) receptors, it was found that browning cells expressed 5HT receptors 2A, 1D, 7 and the upregulation of browning markers was diminished in the presence of exogenous 5HT. Undifferentiated progenitors or completely differentiated beige or white adipocytes did not respond to clozapine administration. The clozapine-induced beige cells displayed increased basal and oligomycin-inhibited (proton leak) oxygen consumption, but these cells showed a lower response to cAMP stimulus as compared with control beige adipocytes indicating that they are less capable to respond to natural thermogenic anti-obesity cues. Our data altogether suggest that novel pharmacological stimulation of these masked beige adipocytes can be a future therapeutic target for the treatment of SGA-induced weight gain.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
authors.forename: E
authors.initials: E
authors.lastname: Kristóf
authors.affiliation: Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary.
authors.forename: Q-M
authors.initials: QM
authors.lastname: Doan-Xuan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
authors.forename: A K
authors.initials: AK
authors.lastname: Sárvári
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
authors.forename: Á
authors.initials: Á
authors.lastname: Klusóczki
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Fischer-Posovszky
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wabitsch
authors.affiliation: Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Bacso
authors.affiliation: MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary.|Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|Department of Medical Chemistry, University of Debrecen, Debrecen, Hungary.
authors.forename: P
authors.initials: P
authors.lastname: Bai
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Balajthy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.|MTA-DE Stem Cells, Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, Debrecen, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Fésüs
mesh_terms: D000069797:Adipocytes, Beige / Q000187:drug effects*; D052437:Adipocytes, Brown / Q000187:drug effects*; D052438:Adipocytes, White / Q000187:drug effects*; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003024:Clozapine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D005877:Gigantism / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D066292:Lipid Droplets / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010101:Oxygen Consumption / Q000187:drug effects; D010641:Phenotype; D011985:Receptors, Serotonin / Q000235:genetics; D022722:Thermogenesis / Q000187:drug effects; D000071256:Uncoupling Protein 1 / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D004272:DNA, Mitochondrial; D011985:Receptors, Serotonin; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; D000242:Cyclic AMP; D003024:Clozapine