olanzapine and Fatty-Liver

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Topics: AMP-Activated Protein Kinases; Animals; Fatty Acid Synthases; Fatty Liver; Hypothalamus; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Olanzapine; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Weight Gain

Topics: Anthocyanins; Diabetes Mellitus, Type 2; Elaeocarpaceae; Fatty Liver; Glucosides; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Olanzapine; Plant Extracts; Polyphenols

Olanzapine is effective to treat for schizophrenia and other mood disorders, but limited by side effects such as weight gain, dyslipidemia, and liver injury. Obesity in the US is at epidemic levels, and is a significant risk factor for drug-induced liver injury. Obesity incidence in the psychiatric population is even higher than in the US population as a whole. The purpose of this study was to test the hypothesis that obesity worsens olanzapine-induced hepatic injury, and to investigate the potential protective effects of sulforaphane. 8-week old female C57BL/6 mice were fed either a high-fat or low-fat control diet (HFD and LFD). Mice also received either olanzapine (8 mg/kg/d) or vehicle by osmotic minipump for 4 weeks. A subset of mice in the HFD + olanzapine group was administered sulforaphane, a prototypical Nrf2 inducer (90 mg/kg/d). Olanzapine alone increased body weight, without a commensurate increase in food consumption. Olanzapine also caused hepatic steatosis and injury. Combining olanzapine and HFD caused further dysregulation of glucose and lipid metabolism. Liver damage from concurrent HFD and olanzapine was worse than liver damage from high-fat diet or olanzapine alone. Sulforaphane alleviated many metabolic side effects of olanzapine and HFD. Taken together, these data show that olanzapine dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by eating a HFD. Activation of the intrinsic antioxidant defense pathway with sulforaphane can partially prevent these effects of olanzapine and may represent a useful strategy to protect against liver injury.

Topics: Animals; Antioxidants; Antipsychotic Agents; Body Weight; Chemical and Drug Induced Liver Injury; Diet, Fat-Restricted; Diet, High-Fat; Fatty Liver; Female; Humans; Isothiocyanates; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Olanzapine; Oxidative Stress; Prevalence; Sulfoxides

Topics: Adult; Animals; Antipsychotic Agents; Carnitine; Chemical and Drug Induced Liver Injury; Coenzyme A Ligases; Dogs; Fatty Acid-Binding Proteins; Fatty Liver; Female; Hep G2 Cells; Hepatocytes; Humans; Liver; Madin Darby Canine Kidney Cells; Male; Mice, Inbred C57BL; Olanzapine; Solute Carrier Family 22 Member 5; Up-Regulation

Second-generation antipsychotic drug (SGA)-induced metabolic abnormalities, such as dyslipidemia, are a major clinical problem for antipsychotic therapy. Accumulated evidences have shown the efficacy of statins in reducing SGA-induced dyslipidemia, but the underlying mechanisms are unclear. In this study, we explored whether mTOR signaling was involved in olanzapine (OLZ)-induced dyslipidemia as well as the lipid-lowering effects of cotreatment of simvastatin (Sim) in rats. Model rats received OLZ (1.0 mg/kg, t.i.d.) for 7 weeks; from the third week a group of model rats were cotreatment of Sim (3.0 mg/kg, t.i.d.) for 5 weeks. We found that OLZ treatment significantly increased the plasma triglyceride (TG) and total cholesterol (TC) levels, and promoted lipid accumulation in the liver, whereas cotreatment of Sim reversed OLZ-induced dyslipidemia. Hepatic mTORC1 and p-mTORC1 expression was accelerated in the OLZ treatment group, with upregulation of mRNA expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, whereas these alterations were ameliorated by Sim cotreatment. In HepG2 cells, rapamycin (a mTOR inhibitor) significantly reduced the OLZ-stimulated hepatocellular lipid contents and weakened the ability of Sim to lower lipids via a mechanism associated with the upregulation of SREBP1c-mediated de novo lipogenesis. Our data suggest that OLZ induces lipid accumulation in both plasma and liver, and Sim ameliorates OLZ-induced lipid metabolic dysfunction through its effects on mTOR signaling via reducing SREBP1c activation and the downregulation of gene expression involved in lipogenesis. These data provide a new insight into the prevention of metabolic side effects induced by antipsychotic drugs.

Topics: Animals; Down-Regulation; Dyslipidemias; Fatty Liver; Female; Hep G2 Cells; Humans; Lipogenesis; Liver; Olanzapine; Rats, Sprague-Dawley; Signal Transduction; Simvastatin; Sterol Regulatory Element Binding Protein 1; TOR Serine-Threonine Kinases

Clinical use of the antipsychotic drug olanzapine (OLA) is associated with metabolic side effects to variable degrees. N-desmethyl-olanzapine (DMO) is one major metabolite of OLA, but its potential involvement in the metabolic responses remains unclear. Here we examined whether DMO can directly impact the metabolic, endocrinal and inflammatory parameters under conditions of metabolic disturbance. DMO administration (2 mg/kg, i.g.) to high-fat diet induced obesity mice for 4 weeks induced a remarkable loss of body weight and fat mass. DMO improved insulin resistance and energy expenditure in mice, but had no significant effects on dyslipidemia or hepatic steatosis. Moreover, DMO induced morphological changes in the white adipose tissue, accompanied by reduced interleukin-1β (IL-1β) production and increased UCP1 expression. These findings demonstrate that DMO is devoid of the metabolic side effects commonly observed for OLA during obesity, which suggests that the N-desmethyl metabolism may function to regulate the metabolic responses to OLA.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Dyslipidemias; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Pirenzepine

Topics: Adult; Alanine Transaminase; Antipsychotic Agents; Aspartate Aminotransferases; Benzodiazepines; Fatty Liver; Hepatomegaly; Humans; Male; Olanzapine; Pirenzepine; Schizophrenia