Abstract
BackgroundSecond generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Sphingolipids play a role in glycaemic balance and insulin resistance. Endoplasmic reticulum (ER) stress contributes to impaired insulin signalling and whole-body glucose intolerance. Diabetogenic SGA effects on ER stress and sphingolipids, such as ceramide and sphingomyelin, in peripheral metabolic tissues are unknown. This study aimed to investigate the acute effects of clozapine and olanzapine on ceramide and sphingomyelin levels, and protein expression of key enzymes involved in lipid and glucose metabolism, in the liver and skeletal muscle.MethodsFemale rats were administered olanzapine (1 mg/kg), clozapine (12 mg/kg), or vehicle (control) and euthanized 1-h later. Ceramide and sphingomyelin levels were examined using electrospray ionization (ESI) mass spectrometry. Expression of lipid enzymes (ceramide synthase 2 (CerS2), elongation of very long-chain fatty acid 1 (ELOVL1), fatty acid synthase (FAS) and acetyl CoA carboxylase 1 (ACC1)), ER stress markers (inositol-requiring enzyme 1 (IRE1) and eukaryotic initiation factor (eIF2α) were also examined.ResultsClozapine caused robust reductions in hepatic ceramide and sphingolipid levels (p < 0.0001), upregulated CerS2 (p < 0.05) and ELOVL1 (+ 37%) and induced significant hyperglycemia (vs controls). In contrast, olanzapine increased hepatic sphingomyelin levels (p < 0.05 vs controls). SGAs did not alter sphingolipid levels in the muscle. Clozapine increased (+ 52.5%) hepatic eIF2α phosphorylation, demonstrating evidence of activation of the PERK/eIF2α ER stress axis. Hepatic IRE1, FAS and ACC1 were unaltered.ConclusionsThis study provides the first evidence that diabetogenic SGAs disrupt hepatic sphingolipid homeostasis within 1-h of administration. Sphingolipids may be key candidates in the mechanisms underlying the diabetes side-effects of SGAs; however, further research is required.
Highlights
Second generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness
Fasting plasma glucose levels An Analysis of Variance (ANOVA) revealed a significant effect of treatment on fasting plasma glucose levels (F2,35 = 15.06, p < 0.0001), with the clozapine group exhibiting significant hyperglycemia compared to the controls (p < 0.0001); no significant differences in glucose levels were observed in the olanzapine treatment group (p > 0.05 vs controls) (Fig. 1)
Sphingolipid levels Ceramide levels There was a significant effect of treatment on total ceramide concentration in the liver (F2,16 = 131.59, p < 0. 0001), with reduced levels following clozapine treatment compared to the controls (p < 0.0001)
Summary
Second generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Olanzapine and clozapine can Weston-Green et al Journal of Biomedical Science (2018) 25:40 critical therapeutic challenge for mental illness and further mechanistic research is required Peripheral tissues, such as the liver, skeletal muscle and adipose tissues, play important roles in metabolic homeostasis and a growing body of literature demonstrates that SGAs target these tissues to induce metabolic side-effects [5,6,7]. Hepatic lipogenesis and subsequent lipid accumulation can be driven by activation of endoplasmic reticulum (ER) stress, thereby contributing to glucometabolic imbalance and leading to reduced insulin signalling and wholebody glucose intolerance [7, 14, 15]. The effect of diabetogenic SGAs on these enzymes is unknown
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