Bardoxolone methyl for the prevention of obesity focusing on the pathology of gut brain adipose axis

University of Wollongong Research Online University of Wollongong Thesis Collection 2017+ University of Wollongong Thesis Collections 2017 Bardoxolone methyl for the prevention of obesity focusing on the pathology of gut-brain-adipose axis Chi Hoang Lan Dinh University of Wollongong Recommended Citation Dinh, Chi Hoang Lan, Bardoxolone methyl for the prevention of obesity focusing on the pathology of gut-brain-adipose axis, Doctor of Philosophy thesis, School of Medicine, University of Wollongong, 2017 http://ro.uow.edu.au/theses1/126 Research Online is the open access institutional repository for the University of Wollongong For further information contact the UOW Library: research-pubs@uow.edu.au Faculty of Science, Medicine and Health Bardoxolone methyl for the prevention of obesity focusing on the pathology of gut-brain-adipose axis CHI HOANG LAN DINH This thesis is presented as part of the requirements for the award of the degree DOCTOR OF PHILOSOPHY From School of Medicine University of Wollongong 2017 ABSTRACT Obesity is major health problem today due to its associated complications such as type diabetes, cardiovascular disease and colon cancer Among these complications there is low grade systemic inflammation, altered gut microbiota as well as an altered autonomic regulation of body metabolism Previous studies have shown that bardoxolone methyl (BARD), a compound derived from oleanolic acid, is capable of reducing inflammation This study systematically examined the preventative effects of BARD on inflammation in various tissues, including visceral white and brown adipose tissues as well as colon tissues, in a chronic high-fat diet induced obesity mouse model Furthermore, this project investigated the effect of BARD on brainstem autonomic regulatory centers Obesity is characterized by increased fat deposition, enlarged adipocytes and fat masses An overload of energy intake induces an inflammatory response, cell stress and altered autonomic function This study showed that BARD treatment prevents high-fat diet induced inflammation This is evidenced by a prevention of macrophage invasion as well as increased pro-inflammatory tumor necrosis factor alpha (TNF-α) and IL-1β in visceral fat tissues such as epidydimal and mesenteric fat masses BARD also prevented the high-fat diet induced increase in intracellular signaling molecules associated with the inflammatory response, including nuclear factor-kappa light-chain enhancer of activated B cells (NF-қB), Akt and ERK, in visceral white adipose tissue The nervous system, including dopamine- peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), UCP2, and AMP-activated protein kinase (AMPK) neuronal signaling, regulates visceral fat mass size Tyrosine hydroxylase (TH) is a biomarker for dopamine production This study showed that BARD stimulates this signaling pathway, from which it prevented excessive deposition of white visceral fat induced by a high-fat diet Interestingly, this study showed that there was virtually no desensitisation effect following a chronic BARD treatment Differing from white adipocytes, brown adipocytes promote energy expenditure, which is beneficial for obesity This study showed that BARD stimulated sympathetic regulation of brainstem autonomic regulatory centers by increasing TH expression and brown adipose tissue i beta 3-adrenergic receptor and PGC-1α signaling In addition, BARD has antiinflammatory effects in brown adipose tissue by promoting the conversion of M1 (CD11c) to M2 (CD260) macrophages and reducing lipid droplet deposition It is known that obesity associated inflammation may be largely due to high-fat diet induced alterations in gut microbiota and leaking gut The colon is extremely important in this regard This study showed that BARD prevented macrophage invasion to the colon tissue, which was induced by a high-fat diet The macrophage biomarker F4/80 was significantly less in the colon of high-fat diet mice treated with BARD compared with vehicle controls Also, this study found that BARD reduced M1 (CD11) but increased M2 (CD260) cells in the colon Furthermore, we found that BARD prevented the high-fat diet induced increase in colonic IL-6, IL-1β and TNF-α Furthermore, this study suggests that BARD may have anti-colon cancer properties as the mice treated with BARD had reduced cyclooxygenase protein, increased IL-10, reduced Ki67 as well as reduced colon thickness, increased colon crypt depth and number of goblet cells per crypt In summary, this mechanistic study examining the effects of BARD in chronic high-fat diet induced obesity has shown that BARD has a number of beneficial effects to visceral white adipose tissues, brown adipose tissues, brainstem and colon tissues and may be a good candidate drug for combating obesity This research, particularly, is leading to new insights of BARD in prevention of inflammation and obesity, as inflammation is one of the culprits causing obesity complications However, an animal study will never be able to replace a human study Even then, a thorough toxicity study must be carried out before a large human clinical trial should be performed ii ACKNOWLEDGEMENTS I like to wish to acknowledge the assistance and support of the following individuals and organisations/institution that helped in the pursuance of this research work: I express my deepest gratitude to my principle supervisor, Prof Xu-Feng Huang, for your valuable ideas, suggestions, guidance and assistance throughout the process of research and thesis writing Thanks for your full support on paper publication so that I can become more confident in scientific research and sound of this great work of art I would like to give the extent whole hearted appreciation and thankfulness to supervisor Dr Alexander Szabo who encouraged me to be independent in pursuing research questions so that I can become an expert in a scientific field of research Thanks again for your enormous patience and unfailing enthusiasm in building up idea, giving comments for method development, editing and correcting my academic and scientific writing in manuscripts and thesis I would also like to thank supervisor Dr Yinghua Yu for technical advice, and giving generous comments for data interpretation and for the revision of manuscripts and thesis Thanks for sharing your expertise in science which helped me a lot in my PhD research and publish my work Thanks Danielle Camer, Qingsheng Zhang, Hongqin Wang, Linda Cohen and all colleagues who made contributions to this project Finally, I would like to thank my friends and staff at University of Wollongong for the numerous ways of support which made my study in Australia more enjoyable My sincere thanks to Can Tho Medical College in my home country for providing me time to pursue my higher degree, the Ministry of Education and Training iii of Vietnam (MOET) and University of Wollongong for financial support during my first three years of 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diet-induced obesity, focusing on the pathology of the gut- brain- adipose. .. effective for the prevention of HFD-induced pathologies in the colon-brainstem -adipose tissue axis of HFD-fed C57BL/6J mice The mechanisms include the suppression of fat deposition, inflammation, oxidative