Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics.
Brown adipose tissue is specialized to burn lipids for thermogenesis and energy expenditure. Second-generation antipsychotics (SGA) are the most commonly used drugs for schizophrenia with several advantages over first-line drugs, however, it can cause clinically-significant weight gain. To reveal the involvement of brown adipocytes in SGA-induced weight gain, we compared the effect of clozapine, quetiapine, and ziprasidone, SGA with different propensities to induce weight gain, on the differentiation and the expression of brown fat-specific markers, lipogenic genes and adipokines in a mouse brown preadipocyte cell line. On Oil Red-O staining, the differentiation was inhibited almost completely by clozapine (40 μM) and partially by quetiapine (30 μM). Clozapine significantly down-regulated the brown adipogenesis markers PRDM16, C/EBPβ, PPARγ2, UCP-1, PGC-1α, and Cidea in dose- and time-dependent manners, whereas quetiapine suppressed PRDM16, PPARγ 2, and UCP-1 much weakly than clozapine. Clozapine also significantly inhibited the mRNA expressions of lipogenic genes ACC, SCD1, GLUT4, aP2, and CD36 as well as adipokines such as resistin, leptin, and adiponectin. In contrast, quetiapine suppressed only resistin and leptin but not those of lipogenic genes and adiponectin. Ziprasidone (10 μM) did not alter the differentiation as well as the gene expression patterns. Our results suggest for the first time that the inhibition of brown adipogenesis may be a possible mechanism to explain weight gain induced by clozapine and quetiapine.
Department of Biochemistry College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Jee-Eun
JE
Oh
Yoon Mi
YM
Cho
Su-Nam
SN
Kwak
Jae-Hyun
JH
Kim
Kyung Won
KW
Lee
Hyosan
H
Jung
Seong-Whan
SW
Jeong
Oh-Joo
OJ
Kwon
D052437:Adipocytes, Brown / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects; D054392:Adipokines / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D000069348:Quetiapine Fumarate; D012559:Schizophrenia / Q000188:drug therapy; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects; D015430:Weight Gain / Q000187:drug effects*
D054392:Adipokines; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D013844:Thiazoles; D000069348:Quetiapine Fumarate; C092292:ziprasidone; D003024:Clozapine