Effects of Cariprazine, Aripiprazole, and Olanzapine on Mouse Fibroblast Culture: Changes in Adiponectin Contents in Supernatants, Triglyceride Accumulation, and Peroxisome Proliferator-Activated Receptor-γ Expression

Abstract

Background and Objectives: The use of the dopamine-partial agonist subclass (also termed dopamine stabilizers) of atypical antipsychotics for the treatment of negative schizophrenia symptoms and some mood disorders has increased recently. Similar to other second-generation antipsychotics (SGAs), aripiprazole (ARI) and cariprazine (CAR) also influence food intake, but the peripheral effects of these drugs on adipose–tissue homeostasis, including adipokine secretion as well as lipo- and adipogenesis, are not fully elucidated. In this study, we explored the adipocyte-related mechanisms induced by second-generation antipsychotics (SGAs), leading to changes in peripheral signals involved in energy homeostasis. Materials and Methods: CAR, a new SGA, was compared with ARI and olanzapine (OLA), using cell cultures to study adipogenesis, and the expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) was measured in adipocytes derived from mouse fibroblasts, by western blotting on days 7, 14, and 21 postinduction. The triglyceride (TG) content of the cells was also evaluated on day 15 using Oil Red O staining, and the adiponectin (AN) content in the cell culture supernatants was quantified on days 7 and 15 by enzyme-linked immunosorbent assay. Cells were treated with two concentrations of ARI (0.5 and 20 µg/mL), OLA (1 and 20 µg/mL), and CAR (0.1 and 2 µg/mL). Results: Both concentrations of ARI and OLA, as well as the lower concentration of CAR, significantly increased the TG contents. The AN levels in the supernatants were significantly increased by the higher concentration of ARI on days 7 and 15 (p < 0.05). Although PPAR-γ levels were not significantly affected by ARI and OLA, the lower concentration of CAR induced a significant time-dependent decrease in PPAR-γ expression (p < 0.05). Conclusions: The in vitro adipogenesis considered from TG accumulation, AN secretion, and PPAR-γ expression was differently influenced by ARI, CAR, and OLA. Understanding the adipocyte-related mechanisms of antipsychotics could contribute to understanding their weight-influencing effect.

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

“…In this view, the reduction of the rates of lipolysis in response to the β-adrenergic agonist isoprenaline was consistently reported in both rats [10] and cultured preadipocytes [14] treated with olanzapine. Moreover, atypical antipsychotics have been described to alter other biological functions of adipocytes, not only related with the management of triglyceride storage/breakdown (lipogenesis and lipolysis) [11,15], but also related to insulin sensitivity and inflammation, such as adipokine secretion [12,14], therefore favoring the onset of insulin resistance. Nevertheless, no functional studies of the lipolytic responses to neuropsychiatric drugs have been performed in human mature adipocytes to date, whereas it has been documented that several antipsychotic drugs alter in vitro gene expression in human mesenchymal stem cells differentiated into adipocytes [2,[16][17][18].…”

“…Previous investigations have been performed by measuring adipocyte biological functions and determining the regulations of key genes involved in metabolic pathways, either in adipocytes from treated animal models [10], or after short-or long-term incubation of cultured adipose cells with psychoactive molecules. To briefly mention examples of such different approaches, it is worth mentioning that the decreased lipolytic effect of isoprenaline and down-regulated hormone-sensitive lipase gene (Hsl) were found in adipocytes from olanzapine-treated rats [10], whereas increased lipid accumulation and adipogenic gene upregulation were observed in cultured adipocytes treated with olanzapine [2,[11][12][13][14]. In this view, the reduction of the rates of lipolysis in response to the β-adrenergic agonist isoprenaline was consistently reported in both rats [10] and cultured preadipocytes [14] treated with olanzapine.…”

“…To briefly mention examples of such different approaches, it is worth mentioning that the decreased lipolytic effect of isoprenaline and down-regulated hormone-sensitive lipase gene (Hsl) were found in adipocytes from olanzapine-treated rats [10], whereas increased lipid accumulation and adipogenic gene upregulation were observed in cultured adipocytes treated with olanzapine [2,[11][12][13][14]. In this view, the reduction of the rates of lipolysis in response to the β-adrenergic agonist isoprenaline was consistently reported in both rats [10] and cultured preadipocytes [14] treated with olanzapine. Moreover, atypical antipsychotics have been described to alter other biological functions of adipocytes, not only related with the management of triglyceride storage/breakdown (lipogenesis and lipolysis) [11,15], but also related to insulin sensitivity and inflammation, such as adipokine secretion [12,14], therefore favoring the onset of insulin resistance.…”

The Role of Adiponectin in the Pathogenesis of Metabolic Disturbances in Patients With Schizophrenia

“…The results of the effect of aripiprazole on adiponectin are inconsistent. An in-vitro study reported that aripiprazole increases blood adiponectin levels in the supernatants on mouse fibroblast cultures ( 120 ). Another in-vitro study revealed that aripiprazole does not change the mRNA expression of ADIPOQ gene on human subcutaneous adipose tissue ( 121 ).…”

Effect on Body Weight and Adipose Tissue by Cariprazine: A Head-to-Head Comparison Study to Olanzapine and Aripiprazole in Rats

“…Concerning the dyslipidemia, the role of PPARs have long been hypothesized [7]. In order to assess the involvement of AT-related mechanisms, we previously measured under in vitro conditions the expression of PPAR-γ after SGA administration during adipogenesis [37]. Although the protein expression (at protein level-measured by Western blot) was not changed under in vitro conditions in the mentioned experience, in 3T3-L1 cell line others found an increase in PPAR-γ expression by Ola [17].…”