Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics

Oh, Jee Eun; Cho, Yoon Mi; Kwak, Su Nam; Kim, Jae Hyun; Lee, Kyungwon; Jung, Hyosan; Jeong, Seong Whan; Kwon, Oh Joo

doi:10.3858/emm.2012.44.9.062

Cited by 26 publications

(17 citation statements)

References 44 publications

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“…In BAT, our gene expression data showed that olanzapine treatment significantly decreased the expression of ten adipogenic or lipogenic genes, without up-regulation of genes involved in lipid metabolism. This is consistent with a recent report from another research group stating that second generation antipsychotics inhibited the expression of a number of adipogenic and lipogenic genes [60]. Our results also showed that the addition of either metformin or berberine restored the expression of eight of these ten genes to near normal levels.…”

Section: Discussionsupporting

confidence: 93%

Metformin and Berberine Prevent Olanzapine-Induced Weight Gain in Rats

Young

Ehli

et al. 2014

PLoS ONE

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Olanzapine is a first line medication for the treatment of schizophrenia, but it is also one of the atypical antipsychotics carrying the highest risk of weight gain. Metformin was reported to produce significant attenuation of antipsychotic-induced weight gain in patients, while the study of preventing olanzapine-induced weight gain in an animal model is absent. Berberine, an herbal alkaloid, was shown in our previous studies to prevent fat accumulation in vitro and in vivo. Utilizing a well-replicated rat model of olanzapine-induced weight gain, here we demonstrated that two weeks of metformin or berberine treatment significantly prevented the olanzapine-induced weight gain and white fat accumulation. Neither metformin nor berberine treatment demonstrated a significant inhibition of olanzapine-increased food intake. But interestingly, a significant loss of brown adipose tissue caused by olanzapine treatment was prevented by the addition of metformin or berberine. Our gene expression analysis also demonstrated that the weight gain prevention efficacy of metformin or berberine treatment was associated with changes in the expression of multiple key genes controlling energy expenditure. This study not only demonstrates a significant preventive efficacy of metformin and berberine treatment on olanzapine-induced weight gain in rats, but also suggests a potential mechanism of action for preventing olanzapine-reduced energy expenditure.

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Section: Discussionsupporting

confidence: 93%

Metformin and Berberine Prevent Olanzapine-Induced Weight Gain in Rats

Young

Ehli

et al. 2014

PLoS ONE

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“…The administration of the drug at 20-fold higher concentration than the upper limit of therapeutic reference range resulted in a significant inhibition of the differentiation of a murine brown preadipocyte cell line. 71 However, toxic effects of the treatment for the cultured cells cannot be excluded at this high clozapine concentration. 47 On the other hand, clozapine administration at the concentrations of therapeutic reference range had a slight positive effect on the expression of the selected BAT marker genes in an in vitro mouse model.…”

Section: Discussionmentioning

confidence: 99%

Clozapine modifies the differentiation program of human adipocytes inducing browning

et al. 2016

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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.

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“…A study showed that Clozapine (40 µM) inhibited resistin mRNA expression in mouse brown adipocytes (76). However, in 121 schizophrenia patients treated with clozapine (403 mg/day), high serum levels of resistin were associated with smokers in comparison with non-smokers (77).…”

Section: Clozapinementioning

confidence: 96%

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

et al. 2020

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Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders.

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Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics

Cited by 26 publications

References 44 publications

Metformin and Berberine Prevent Olanzapine-Induced Weight Gain in Rats

Metformin and Berberine Prevent Olanzapine-Induced Weight Gain in Rats

Clozapine modifies the differentiation program of human adipocytes inducing browning

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

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