Jiamei Lian

Risperidone is a commonly used antipsychotic drug in juveniles, but with serious metabolic side-effects. Previous evidence suggests that exercise mitigates risperidone-induced hypertriglyceridemia and adipose accumulation, yet the underlying hepatic mechanisms remain unclear. In this study, female juvenile rats were randomly assigned to four groups (n = 8/group): Vehicle + Sedentary, Risperidone (0.9 mg/kg, twice daily) + Sedentary, Vehicle + Exercise (3-hour voluntary access to a running wheel/day), and Risperidone + Exercise groups (n = 8/group). Following 4-week treatment, liver tissue was harvested for subsequent analyses. Risperidone increased hepatic expression of fatty acid synthase (FAS) and upstream stimulatory factor 1 (USF1), while exercise attenuated these changes and elevated the pAMPK/AMPK ratio, indicating suppressed lipogenesis. Risperidone also upregulated peroxisome proliferator-activated receptor γ (PPARγ) and CD36, promoting lipid uptake and storage; these effects were reversed by exercise, which additionally reduced FSP27 expression. Furthermore, exercise enhanced lipolytic and β-oxidative capacity, as evidenced by increased adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and restoration of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) levels suppressed by risperidone. Collectively, risperidone promotes hepatic lipid accumulation by stimulating USF1/FAS-mediated lipogenesis and PPARγ/CD36-driven uptake while suppressing the PGC1α signaling pathway associated with β-oxidation. Voluntary exercise counteracts these alterations, thereby ameliorating risperidone-induced hepatic lipid dysregulation.

Olanzapine and clozapine, two of the most efficacious second-generation antipsychotic drugs (SGAs), are known to cause serious metabolic side effects. Despite their clinical utility, the epigenetic basis of these metabolic side-effects remains poorly understood. This exploratory study investigated whether histone methylation is associated with metabolic disorders following chronic SGA treatment. Rats were treated with olanzapine or clozapine for 9 weeks and then sacrificed 2 h after the final treatment. After evaluating the metabolic parameters, Chromatin immunoprecipitation (ChIP)-deep sequencing was conducted on liver tissue pooled from twelve samples per group to quantify histone H3K4me2 methylation and transcriptional changes. Gene ontology term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to explore shared functional pathways of genes with differential histone methylation. Key findings revealed that both olanzapine and clozapine induced widespread changes in hepatic histone methylation, particularly hypermethylation at H3K4me2 across genes involved in lipid and glucose metabolism, insulin signalling, and adipogenesis. Olanzapine- and clozapine-treated rats displayed increased H3K4me2 levels at numerous gene loci and at distinct genomic regions. These findings suggest the importance of monitoring metabolic parameters in psychiatric patients and potential novel strategies to mitigate SGA-induced metabolic side effects.

Olanzapine is an atypical antipsychotic drug and a potent muscarinic M3 receptor (M3R) antagonist. Olanzapine has been reported to cause metabolic disorders, including dyslipidemia. Anaplastic lymphoma kinase (Alk), a tyrosine kinase receptor well known in the pathogenesis of cancer, has been recently identified as a key gene in the regulation of thinness via the regulation of adipose tissue lipolysis. This project aimed to investigate whether Olanzapine could modulate the hepatic Alk pathway and lipid metabolism via M3R. Female rats were treated with Olanzapine and/or Cevimeline (an M3R agonist) for 9 weeks. Lipid metabolism and hepatic Alk signaling were analyzed. Nine weeks’ treatment of Olanzapine caused metabolic disturbance including increased body mass index (BMI), fat mass accumulation, and abnormal lipid metabolism. Olanzapine treatment also led to an upregulation of Chrm3, Alk, and its regulator Ptprz1, and a downregulation of Lmo4, a transcriptional repressor of Alk in the liver. Moreover, there were positive correlations between Alk and Chrm3, Alk and Ptprz1, and a negative correlation between Alk and Lmo4. However, cotreatment with Cevimeline significantly reversed the lipid metabolic disturbance and adipose tissue accumulation, as well as the upregulation of the hepatic Alk signaling caused by Olanzapine. This study demonstrates evidence that Olanzapine may cause metabolic disturbance by modulating hepatic Alk signaling via M3R, which provides novel insight for modulating the hepatic Alk signaling and potential interventions for targeting metabolic disorders.

As a partial histamine H1 receptor agonist and H3 antagonist, betahistine has been reported to partially prevent olanzapine-induced dyslipidemia and obesity through a combination therapy, although the underlying epigenetic mechanisms are still not known. Recent studies have revealed that histone regulation of key genes for lipogenesis and adipogenesis in the liver is one of the crucial mechanisms for olanzapine-induced metabolic disorders. This study investigated the role of epigenetic histone regulation in betahistine co-treatment preventing dyslipidemia and fatty liver caused by chronic olanzapine treatment in a rat model. In addition to abnormal lipid metabolism, the upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPα), as well as the downregulation of carnitine palmitoyltransferase 1A (CPT1A) in the liver induced by olanzapine, were significantly attenuated by betahistine co-treatment. In addition, betahistine co-treatment significantly enhanced the global expression of H3K4me and the enrichment of H3K4me binding on the promoter of Cpt1a gene as revealed by ChIP-qPCR, but inhibited the expression of one of its site-specific demethylases, lysine (K)-specific demethylase 1A (KDM1A). Betahistine co-treatment also significantly enhanced the global expression of H3K9me and the enrichment of H3K9me binding on the promoter of the Pparg gene, but inhibited the expression of two of its site-specific demethylases, lysine demethylase 4B (KDM4B) and PHD finger protein 2 (PHF2). These results suggest that betahistine attenuates abnormal adipogenesis and lipogenesis triggered by olanzapine through modulating hepatic histone methylation, and thus inhibiting the PPARγ pathway-mediated lipid storage, while at the same time promoting CP1A-mediated fatty acid oxidation.

The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABA_A receptors and AKT-GSK3β signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal the pathological changes in these biomarkers and antipsychotic modulations in the VTA. Using a juvenile polyriboinosinic-polyribocytidylic acid (Poly I:C) psychiatric rat model, this study investigated the effects of adolescent risperidone treatment on GABA_A receptors and AKT/GSK3β in the VTA. Pregnant female Sprague–Dawley rats were administered Poly I:C (5mg/kg; i.p) or saline at gestational day 15. Juvenile female offspring received risperidone (0.9 mg/kg, twice per day) or a vehicle from postnatal day 35 for 25 days. Poly I:C offspring had significantly decreased mRNA expression of GABA_A receptor β3 subunits and glutamic acid decarboxylase (GAD2) in the VTA, while risperidone partially reversed the decreased GAD2 expression. Prenatal Poly I:C exposure led to increased expression of AKT2 and GSK3β. Risperidone decreased GABA_A receptor β2/3, but increased AKT2 mRNA expression in the VTA of healthy rats. This study suggests that Poly I:C-elicited maternal immune activation and risperidone differentially modulate GABAergic neurotransmission and AKT-GSK3β signaling in the VTA of adolescent rats.