Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells.
Olanzapine is a second-generation atypical antipsychotic drug (AAPD). Major side effects of olanzapine are weight gain and development of diabetes mellitus, which are risk factors of cardiovascular diseases. The possible causes of metabolic adverse effects are known as poor satiety and increased food intake due to blockade of receptors such as 5-HT(2C) in CNS. In this study, we examine the effect of olanzapine on peripheral adipogenesis using cultured 3T3-L1 cell model. Olanzapine increased triacylglyceride (TG) accumulation during 3T3-L1 preadipocyte differentiation to mature adipocyte phenotype. TG accumulation was accompanied by overexpression of fatty acid synthase and adiponectin that are the downstream genes of sterol regulatory element binding protein-1 (SREBP-1), one of the key transcription factors in lipid homeostasis. We further consisted that mostly SREBP-1 and at a lesser extent peroxisome proliferator-activated receptor gamma (PPAR-gamma), but not CCAAT/enhancer binding protein-alpha (C/EBP-alpha), were overexpressed and activated in 3T3-L1 adipocytes exposed to olanzapine. Furthermore, we showed that olanzapine enhanced the activity of SRE-1-containing LDLR promoter in transfected 3T3-L1 adipocytes and HepG2 cells. Taken together, olanzapine may cause body weight gain not only through influencing CNS receptors, but also affecting the peripheral adipogenesis regulated by SREBP-1.
Yang
Li-Hung
LH
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Chen
Tzer-Ming
TM
Yu
Sung-Tsai
ST
Chen
Yen-Hui
YH
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D000077152:Olanzapine; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation; D015430:Weight Gain / Q000187:drug effects*
D052242:Adiponectin; C499919:Adipoq protein, mouse; D014150:Antipsychotic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D011973:Receptors, LDL; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D001569:Benzodiazepines; D064429:Fatty Acid Synthases; D000077152:Olanzapine