Clozapine worsens glucose intolerance, nonalcoholic fatty liver disease, kidney damage and retinal injury and increases renal reactive oxygen species production and chromium loss in obese mice
Journal
International Journal of Molecular Sciences
Journal Volume
22
Journal Issue
13
Date Issued
2021
Author(s)
Chang G.-R
Liu H.-Y
Wang C.-M
Wu C.-F
Lin J.-W
Lin W.-L
Wang Y.-C
Lin T.-C
Liao H.-J
Hou P.-H
Chan C.-H
Lin C.-F.
Abstract
Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozap-ine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver dam-age, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food effi-ciency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin re-sistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 ex-pression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione pe-roxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention. ? 2021 by the author. Licensee MDPI, Basel, Switzerland.
Subjects
Chromium
Clozapine
Fatty liver disease
Glucose intolerance
Obesity
Reactive oxygen species
Renal damage
Retinal injury
adiponectin
alanine aminotransferase
antioxidant
aspartate aminotransferase
biological marker
catalase
chromium
clozapine
creatinine
fatty acid binding protein 4
fatty acid synthase
glucose
glucose transporter 4
glutathione peroxidase
immunoglobulin enhancer binding protein
inducible nitric oxide synthase
insulin
interleukin 1
messenger RNA
protein kinase B
protein PNPLA3
reactive oxygen metabolite
sterol regulatory element binding protein 1
superoxide dismutase
triacylglycerol
unclassified drug
FABP4 protein, human
fatty acid binding protein
NOS2 protein, human
SREBF1 protein, human
alanine aminotransferase blood level
animal experiment
animal model
animal tissue
Article
aspartate aminotransferase blood level
body weight gain
controlled study
creatinine blood level
diabetes mellitus
disease exacerbation
epididymis fat
food intake
glucose homeostasis
glucose intolerance
hyperglycemia
insulin blood level
insulin resistance
insulin sensitivity
kidney disease
kidney injury
lipid diet
lipid liver level
liver function
liver injury
male
morphometry
mouse
mRNA expression level
nonalcoholic fatty liver
nonhuman
obesity
protein expression level
protein phosphorylation
real time polymerase chain reaction
regulatory mechanism
retina cell
retina injury
retinal thickness
retinopathy
retroperitoneal fat pad
signal transduction
thickness
triacylglycerol blood level
urea nitrogen blood level
urinary excretion
adipocyte
animal
complication
disease model
fluorescent antibody technique
gene expression
gene expression regulation
genetics
immunohistochemistry
liver
metabolism
mouse mutant
retina disease
Adipocytes
Animals
Biomarkers
Body Weights and Measures
Disease Models, Animal
Fatty Acid-Binding Proteins
Fluorescent Antibody Technique
Gene Expression
Gene Expression Regulation
Glucose Intolerance
Immunohistochemistry
Insulin
Kidney Diseases
Liver
Mice
Mice, Obese
Nitric Oxide Synthase Type II
Non-alcoholic Fatty Liver Disease
Proto-Oncogene Proteins c-akt
Reactive Oxygen Species
Retinal Diseases
Sterol Regulatory Element Binding Protein 1
SDGs
Type
journal article