Abstract
BackgroundMetabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined.Methodology/Principal FindingsCultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 µM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line.Conclusions/SignificanceClozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.
Highlights
This study addresses the cellular and molecular basis of a highly significant public health problem: metabolic syndrome (MetS)
There is a growing consensus in the obesity and diabetes fields that understanding the mechanisms responsible for the adverse metabolic effects of atypical antipsychotics may shed an important light on the origin of Metabolic syndrome (MetS), and this is the rationale for using this model in the current study
We examined whether clozapine induced changes in mitochondria morphology, membrane potential, and mitochondria volume in the insulin-responsive cell types as these types of changes are thought to underlie the pathogenesis of several metabolic diseases [29]
Summary
This study addresses the cellular and molecular basis of a highly significant public health problem: metabolic syndrome (MetS). Recent estimates indicate that independent of cardiovascular disease, risk factors associated with MetS cost an estimated $80 billion annually [6] and are projected to increase between 59% and 157% by 2020 [7] Because of this significant health problem and its economic burden, there is a great need to better understand the cellular and molecular basis of MetS. Metabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. An atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. The effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined
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