Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat

Abstract

Objective: This study aims to investigate whether orexigenic antipsychotic drugs may induce dyslipidemia and glucose disturbances in female rats through direct perturbation of metabolically active peripheral tissues, independent of prior weight gain.

Methods: In the current study, we examined whether a single intraperitoneal injection of clozapine or olanzapine induced metabolic disturbances in adult female outbred Sprague-Dawley rats. Serum glucose and lipid parameters were measured during time-course experiments up to 48 h. Real-time quantitative PCR was used to measure specific transcriptional alterations in lipid and carbohydrate metabolism in adipose tissue depots or in the liver.

Results: Our results demonstrated that acute administration of clozapine or olanzapine induced a rapid, robust elevation of free fatty acids and glucose in serum, followed by hepatic accumulation of lipids evident after 12-24 h. These metabolic disturbances were associated with biphasic patterns of gluconeogenic and lipid-related gene expression in the liver and in white adipose tissue depots.

Conclusion: Our results support that clozapine and olanzapine are associated with primary effects on carbohydrate and lipid metabolism associated with transcriptional changes in metabolically active peripheral tissues prior to the development of drug-induced weight gain.

Fig. 1

The effect of clozapine and olanzapine on serum free fatty acid (FFA) levels. The serum levels of FFAs were measured in rats exposed to a clozapine (25 m/kg; dark bars) or vehicle (lactic acid; 6 μg/ml; light bars) or b olanzapine (5 m/kg; dark bars) or vehicle (lactic acid; 6 μg/ml; light bars). The levels were measured at 0.25, 0.5, 1, 3, 6, 12, 24, and 48 h in the clozapine experiment (n = 5) and at 1, 3, 6, 12, and 24 h in the olanzapine experiment (n = 9). **p < 0.01; ***p < 0.001

Fig. 2

The effect of clozapine and olanzapine on serum glucose level. The serum levels of glucose were measured in rats exposed to a clozapine (25 m/kg; dark bars) or vehicle (lactic acid; 6 μg/ml; light bars) or b olanzapine (5 m/kg; dark bars) or vehicle (lactic acid; 6 μg/ml; light bars). The levels were measured at 0.25, 0.5, 1, 3, 6, 12, 24, and 48 h in the clozapine experiment (n = 5) and at 1, 3, 6, 12, and 24 h in the olanzapine experiment (n = 9). **p < 0.01; ***p < 0.001

Fig. 3

The effect of clozapine and olanzapine on genes involved in gluconeogenesis and insulin signaling. Relative gene expression of a Pepck, b Pgc1a, and c Irs2 in the liver from rats exposed to clozapine (25 m/kg) and d Pepck, e Pgc1a, and f Irs2 in the liver from rats exposed to olanzapine (5 mg/kg), measured as fold change (mean ± SEM) relative to vehicle-exposed rats. The expression levels were normalized relative to the expression of the ribosomal gene P0. The relative levels were measured at 0.25, 0.5, 1, 3, 6, 12, 24, and 48 h in the clozapine experiment (n = 5) and at 1, 3, 6, 12, and 24 h in the olanzapine experiment (n = 9). *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 4

The effect of clozapine on lipogenic genes in mesenteric WAT. Relative gene expression in mesenteric fat of a Srebp1c, b Fasn, c Srebp2, and d Hmgcr, measured as fold change (mean ± SEM) in clozapine- (25 m/kg) relative to vehicle-exposed rats. The expression levels were normalized relative to the expression of the ribosomal gene P0. The relative levels were measured at 0.25, 0.5, 1, 3, 6, 12, 24, and 48 h, with each data point representative of n = 5 animals. *p < 0.05; **p < 0.01

Fig. 5

Transcriptional effects in liver of subsequent injections with clozapine. Relative expression levels of a Soat1, b Fasn, c Pepck, and d Irs2, following two subsequent injections, containing either vehicle (lactic acid; 6 μg/ml) or clozapine (25 mg/kg) in various combinations. The injections were administered 12 and 1 h before killing, in the following combinations: Ctrl (vehicle 12 h/vehicle 1 h), clozapine 1 h (vehicle 12 h/clozapine 1 h), clozapine 12 h (clozapine 12 h/vehicle 1 h), and clozapine 12 + 1 h (clozapine 12 h/clozapine 1 h). The expression levels were normalized relative to the expression of the ribosomal gene P0. Each data point representative of n = 5 animals. *p < 0.05; **p < 0.01; ***p < 0.001