Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration

Weston-Green, Katrina; Babic, Ilijana; Santis, Michael De; Pan, Bo; Montgomery, Magdalene K.; Mitchell, Todd W.; Huang, Xu-Feng; Nealon, Jessica R.

doi:10.1186/s12929-018-0437-1

Cited by 19 publications

(24 citation statements)

References 66 publications

(97 reference statements)

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“…In a similar study, adult male Wistar rats treated with intragastric olanzapine infusion (30 mg/kg/h) and subjected to either “low” (continuous infusion of insulin at 3 mU/kg/min) or “high” (9 mU/kg/min) HEC analysis showed reduced GIR and hepatic glycogen content, with an increase in HGO detected in the high insulin-infusion group [109]. Another single-dose study described that hepatic glycogen content in fasted female Sprague-Dawley rats was reduced in the first hour after oral administration of clozapine (12 mg/kg), and the rats also developed hyperglycemia [110]. In the setting of repeated dose-experiments, a study in female Sprague-Dawley rats chronically treated with olanzapine (2.0 or 7.5 mg/kg) via osmotic mini-pumps for 4 weeks followed by HEC analysis (insulin infusion at 5 mU/kg/h) revealed reduced GIR and increased HGO in both treatment groups compared with control rats [111].…”

Section: New Insights Into the Molecular Mechanisms By Which Sgas mentioning

confidence: 99%

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

Grajales

Ferreira

Valverde

2019

Cells

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Second-generation antipsychotics (SGAs) are the cornerstone of treatment for schizophrenia because of their high clinical efficacy. However, SGA treatment is associated with severe metabolic alterations and body weight gain, which can increase the risk of type 2 diabetes and cardiovascular disease, and greatly accelerate mortality. Several underlying mechanisms have been proposed for antipsychotic-induced weight gain (AIWG), but some studies suggest that metabolic changes in insulin-sensitive tissues can be triggered before the onset of AIWG. In this review, we give an outlook on current research about the metabolic disturbances provoked by SGAs, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances. Specifically, we discuss the mechanistic insights gleamed from cellular and preclinical animal studies that have reported on the impact of SGAs on insulin signaling, endogenous glucose production, glucose uptake and insulin secretion in the liver, skeletal muscle and the endocrine pancreas. Finally, we discuss some of the genetic and epigenetic changes that might explain the different susceptibilities of SGA-treated patients to the metabolic side-effects of antipsychotics.

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Section: New Insights Into the Molecular Mechanisms By Which Sgas mentioning

confidence: 99%

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

Grajales

Ferreira

Valverde

2019

Cells

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“…This study identified trend correlations between peripheral lipid and glucose measures as well. Additionally, relevant to our study in the skeletal muscle, Weston-Green and colleagues found no effect of 1-hour AAP treatment on CER muscle levels in female rats; however, they did identify decreases in hepatic CER levels [52]. Within our study, we identified elevated levels of skeletal muscle CERs in the AAP group relative to those in the mood stabilizer group, which may align with studies in the metabolic literature that have demonstrated increased skeletal muscle CERs with insulin resistance [53].…”

Section: Discussionmentioning

confidence: 82%

Atypical Antipsychotics and the Human Skeletal Muscle Lipidome

et al. 2018

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Atypical antipsychotics (AAPs) are a class of medications associated with significant metabolic side effects, including insulin resistance. The aim of this study was to analyze the skeletal muscle lipidome of patients on AAPs, compared to mood stabilizers, to further understand the molecular changes underlying AAP treatment and side effects. Bipolar patients on AAPs or mood stabilizers underwent a fasting muscle biopsy and assessment of insulin sensitivity. A lipidomic analysis of total fatty acids (TFAs), phosphatidylcholines (PCs) and ceramides (CERs) was performed on the muscle biopsies, then lipid species were compared between treatment groups, and correlation analyses were performed with insulin sensitivity. TFAs and PCs were decreased and CERs were increased in the AAP group relative to those in the mood stabilizer group (FDR q-value <0.05). A larger number of TFAs and PCs were positively correlated with insulin sensitivity in the AAP group compared to those in the mood stabilizer group. In contrast, a larger number of CERs were negatively correlated with insulin sensitivity in the AAP group compared to that in the mood stabilizer group. The findings here suggest that AAPs are associated with changes in the lipid profiles of human skeletal muscle when compared to mood stabilizers and that these changes correlate with insulin sensitivity.

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“…Olanzapine promotes adipocyte differentiation, lipid droplet deposition, macrophage infiltration, and inflammation in white adipose tissues, while reducing brown adipose thermogenesis [10,11,12,13,17,18,19,21,25]. Hepatic lipogenesis and impaired lipid metabolism are other targets of olanzapine action [8,20,21,22,38,39]. The hypothalamus, liver, and adipose tissues represent critical central and peripheral organs for the actions of insulin.…”

Section: Discussionmentioning

confidence: 99%

Olanzapine Induced Dysmetabolic Changes Involving Tissue Chromium Mobilization in Female Rats

Yang¹,

Wang

Lin³

et al. 2019

IJMS

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Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

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Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration

Cited by 19 publications

References 66 publications

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

Atypical Antipsychotics and the Human Skeletal Muscle Lipidome

Olanzapine Induced Dysmetabolic Changes Involving Tissue Chromium Mobilization in Female Rats

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