title: Bardoxolone methyl prevents insulin resistance and the development of hepatic steatosis in mice fed a high-fat diet.
abstract: High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that bardoxolone methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR. BM prevented HF diet-induced insulin resistance and alterations in the protein levels of protein tyrosine phosphatase 1B (PTP1B), forkhead box protein O1 (FOXO1) and BDNF, and expression of the insulin receptor (IR), IRS-1 and glucose-6-phosphatase (G6Pase) genes. Furthermore, BM prevented fat accumulation in the liver and decreases in the β-oxidation gene, peroxisomal acyl-coenzyme A oxidase 1 (ACOX) in mice fed a HF diet. In the livers of HF fed mice, BM administration prevented HF diet-induced macrophage infiltration, inflammation as indicated by reduced IL-6 and signal transducer and activator of transcription 3 (STAT3) protein levels and TNFα mRNA expression, and increased nuclear factor-like 2 (Nrf2) mRNA expression and nuclear protein levels. These findings suggest that BM prevents HF diet induced insulin resistance and the development of hepatic steatosis in mice fed a chronic HF diet through modulation of molecules involved in insulin signalling, lipid metabolism and inflammation in the liver.
authors.affiliation: Centre for Translational Neuroscience, Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Camer
authors.affiliation: Centre for Translational Neuroscience, Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Centre for Translational Neuroscience, Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia; ANSTO LifeSciences, Australian Nuclear Science and Technology Organisation, NSW 2234, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Szabo
authors.affiliation: Centre for Translational Neuroscience, Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia.
authors.forename: Chi H L
authors.initials: CH
authors.lastname: Dinh
authors.affiliation: Centre for Translational Neuroscience, Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Centre for Translational Neuroscience, Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia.
authors.forename: Licai
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Centre for Translational Neuroscience, Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia. Electronic address: xhuang@uow.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000818:Animals; D002465:Cell Movement; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000209:etiology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007328:Insulin; D009828:Oleanolic Acid; C445068:bardoxolone methyl
keywords: Bardoxolone methyl; Hepatic steatosis; High fat diet; Insulin resistance; Obesity