Effects of clozapine on adipokine secretions/productions and lipid droplets in 3T3-L1 adipocytes

Abstract

Clozapine, a second-generation antipsychotic (SGA), is a cause of side effects related to metabolic syndrome. The participation of serotonin 5-HT and histamine H receptors in the central nervous system has been reported as a mechanism of the weight gain caused by clozapine. In the present study, we investigated the direct pharmacological action of clozapine on the 3T3-L1 adipocytes and compared it to that of blonanserin, an SGA with low affinity for both receptors. Short-term exposure to clozapine decreased secretion and mRNA expression of leptin. Long-term exposure decreased leptin as well as adiponectin secretion, and further increased lipid droplets accumulation. However, short- and long-term exposures to blonanserin did not affect these parameters. A selective serotonin 5-HT, but not a histamine H, receptor antagonist enhanced the decreased secretion of leptin induced by short-term exposure to clozapine, but did not affect the increased accumulation of lipid droplets. Our findings indicate that clozapine, but not blonanserin, strongly and directly affected the secretion of adipokines, such as leptin, in adipocytes and caused adipocyte enlargement.

Leptin and psychiatric illnesses: does leptin play a role in antipsychotic-induced weight gain?

“…Indeed, in their study, short and long-term exposure to clozapine significantly decreased secretion of leptin and its mRNA expression [91]. More specifically, while investigating the mechanisms of this decreased metabolism of leptin pertaining to clozapine, the authors found that a selective serotonin 5-HT2c antagonism significantly enhances the lowered secretion of leptin triggered by clozapine when compared to controls [91]. According to their findings, this was not the case for histamine H1 antagonism [91].…”

“…They concluded that clozapine, but not blonanserin, strongly and directly interacts with leptin secretion (as well as other adipokines' secretion) and adipocytes enlargement. Thus, this drug's effect on metabolic disturbances is also linked to a direct action on adipocytes mechanism of the regulation of food intake [91]. Indeed, in their study, short and long-term exposure to clozapine significantly decreased secretion of leptin and its mRNA expression [91].…”

“…They hypothesized that this elevation could theoretically signal to the brain the immediate need for appetite suppression and/or increase in the energy expenditure to counteract the incoming disturbance of the metabolic state induced by clozapine [86]. Recently, Tsubai et al assessed the expression of adipokines in mature 3 T3-L1 adipocytes cultured with clozapine and found a causal role for histamine H1/serotonin 5-HT2c receptors [91]. They concluded that clozapine, but not blonanserin, strongly and directly interacts with leptin secretion (as well as other adipokines' secretion) and adipocytes enlargement.…”

“…Thus, this drug's effect on metabolic disturbances is also linked to a direct action on adipocytes mechanism of the regulation of food intake [91]. Indeed, in their study, short and long-term exposure to clozapine significantly decreased secretion of leptin and its mRNA expression [91]. More specifically, while investigating the mechanisms of this decreased metabolism of leptin pertaining to clozapine, the authors found that a selective serotonin 5-HT2c antagonism significantly enhances the lowered secretion of leptin triggered by clozapine when compared to controls [91].…”

“…More specifically, while investigating the mechanisms of this decreased metabolism of leptin pertaining to clozapine, the authors found that a selective serotonin 5-HT2c antagonism significantly enhances the lowered secretion of leptin triggered by clozapine when compared to controls [91]. According to their findings, this was not the case for histamine H1 antagonism [91]. Similarly, while studying the dynamics of serum leptin level and some anthropometric values in patients with schizophrenia and treated by risperidone, olanzapine and clozapine, Gorobets and collaborators' results suggested that leptin resistance contributes to the pharmacogenetic increment of body weight [87,92].…”