Berberine inhibits SREBP‐1‐related clozapine and risperidone induced adipogenesis in 3T3‐L1 cells

Abstract

Weight gain is a common and potentially serious complication associated with the treatment of second generation antipsychotics such as clozapine and risperidone. Increased peripheral adipogenesis via the SREBP-1 pathway could be one critical mechanism responsible for antipsychotic drug-induced weight gain. Berberine, a botanical alkaloid, has been shown in our previous studies to inhibit adipogenesis in cell and animal models. MTT was used to determine the cytotoxic effects of clozapine and risperidone in combination with berberine. Differentiation of 3T3-L1 cells was monitored by Oil-Red-O staining and the expression of SREBP-1 and related proteins was determined by real-time RT-PCR and western blotting. The results showed that neither clozapine nor risperidone, alone or in combination with berberine had significant effects on cell viability. Eight days treatment with 15 μM clozapine increased adipogenesis by 37.4% and 50 μM risperidone increased adipogenesis by 26.5% during 3T3-L1 cell differentiation accompanied by increased SREBP-1, PPARγ, C/EBPα, LDLR and Adiponectin gene expression. More importantly, the addition of 8 μM berberine diminished the induction of adipogenesis almost completely accompanied by down-regulated mRNA and protein expression levels of SREBP-1-related proteins. These encouraging results may lead to the use of berberine as an adjuvant to prevent weight gain during second generation antipsychotic medication.

Berberine Alleviates Olanzapine-Induced Adipogenesis via the AMPKα–SREBP Pathway in 3T3-L1 Cells

“…Recently, it was reported that BBR could inhibit adipogenesis induced by clozapine and risperidone through the SREBP-1-related pathway in 3T3-L1 cells [28]. BBR can also prevent weight gain induced by OLZ via the UCP-1-related pathway in rats [39].…”

“…Accumulated evidence has shown that BBR can reduce lipogenesis in vitro and in vivo through a series of mechanisms, including the downregulation of the expression of peroxisome proliferator activated receptor γ (PPARγ) [27]. Although BBR has been reported to inhibit clozapine and risperidone-induced adipogenesis via SREBP-1 in 3T3-L1 cells [28], it is unclear whether SREBP-2 plays a role in the BBR restraint of OLZ-induced adipogenesis. Likewise, BBR ameliorates lipid dysregulation in obesity by managing the activity of peripheral and central AMPKα [29].…”

Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats

“…Interestingly, it was recently demonstrated that clozapine and risperidone elicited significant inductions of SREBP-1 maturation and FASN mRNA expression in primary cultures of rat hepatocytes and 3T3-L1 cells associated with an increase of triacylglycerol (Hu et al 2010;Lauressergues et al 2011). Therefore, it is also important in further study to compare the effects of these antipsychotics on inducing SREBP-controlled transcriptional activation of lipogenesis in the liver and WAT.…”

Association between SREBF2 gene polymorphisms and metabolic syndrome in clozapine-treated patients with schizophrenia

“…Indeed, recent reports have demonstrated that atypical antipsychotic drugs could activate the SREBP transcription factors, with subsequent transcriptional upregulation of downstream cholesterol and fatty acid biosynthesis in various cellular and animal models exposed to antipsychotics (Canfran-Duque et al, 2013;Hu et al, 2010;Lauressergues et al, 2010Lauressergues et al, , 2011.…”