Exp Mol Med.  2012 Sep;44(9):545-553.

Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics

• Oh JE
• Cho YM
• Kwak SN
• Kim JH
• Lee KW
• Jung H
• Jeong SW
• Kwon OJ

Abstract

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 microM) and partially by quetiapine (30 microM). Clozapine significantly down-regulated the brown adipogenesis markers PRDM16, C/EBPbeta, PPARgamma2, UCP-1, PGC-1alpha, and Cidea in dose- and time-dependent manners, whereas quetiapine suppressed PRDM16, PPARgamma2, 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 microM) 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.

Keyword

adipocytes, brown; adipogenesis; antipsychotic agents; PPAR gamma; PRDM16 protein, human

MeSH Terms

Adipocytes, Brown/drug effects
Adipogenesis/drug effects
Adipokines/metabolism
Animals
*Antipsychotic Agents/administration & dosage/adverse effects
Cell Differentiation/drug effects
Cell Line
Cell Survival/drug effects
*Clozapine/administration & dosage/adverse effects
*Dibenzothiazepines/administration & dosage/adverse effects
Gene Expression Regulation/drug effects
Humans
Mice
*Piperazines/administration & dosage/adverse effects
Schizophrenia/drug therapy
*Thiazoles/administration & dosage/adverse effects
Weight Gain/*drug effects