title: Bardoxolone methyl prevents obesity and hypothalamic dysfunction.
abstract: High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation.
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia. Electronic address: dc608@uowmail.edu.au.
authors.forename: Danielle
authors.initials: D
authors.lastname: Camer
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia; ANSTO Life Sciences, Australian Nuclear Science and Technology Organisation, NSW, 2234, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Szabo
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.
authors.forename: Chi H L
authors.initials: CH
authors.lastname: Dinh
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D020738:Leptin / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents; D020738:Leptin; D009828:Oleanolic Acid; C445068:bardoxolone methyl
keywords: Energy balance; High-fat diet; Hypothalamus; Inflammation; Leptin signalling; Obesity