Plant-derived celastrol ameliorates metabolic dysfunctions, oxidative stress and inflammation in diet-induced obesity via disrupting the cross-talk between PKM2, HIF-1α and IL-1β

Dr Rong, Jianhui   (Principal Investigator (PI))

Professor Li Xuechen   (Co-Investigator)

Professor Wang Yu   (Co-Investigator)

Dr Xia Zhengyuan   (Co-Investigator)

36

2018-01-01

1229089

Plant-derived celastrol ameliorates metabolic dysfunctions, oxidative stress and inflammation in diet-induced obesity via disrupting the cross-talk between PKM2, HIF-1α and IL-1β

Cardiovascular disease, Chinese medicine celastrol, Molecular mechanism, Obesity, Pyruvate kinase M2

Traditional Chinese Medicine (basic),Pharmacology/Toxicology

Biology and Medicine (M)

17100317

General Research Fund (GRF)

2017

Completed

1 To determine the effects of celastrol on the lipid metabolism, oxidative stress and inflammation in diet-induced obese mice. Our pilot experiments suggest that celastrol may promote weight loss via inducing lipolytic and antioxidant enzymes while inhibiting lipogenesis and inflammation. We will determine the effects of celastrol on the expression of key biomarkers in lipid metabolism, redox homeostasis and inflammation in diet-induced obese mice by Western blotting and qRT-PCR. We will analyze lipid composition by GC-MS technique. 2 To measure the impact of covalent celastrol-PKM2 conjugation on the cellular signals involving PKM2, HIF-1α and IL-1β in macrophages and adipocytes. We discovered that celastrol not only formed covalent conjugate with PKM2 but also suppressed the expression of HIF-1α and phospho-STAT3 in macrophages. We hypothesize that celastrol may attenuate hypoxic and inflammatory signals via covalent inhibition of PKM2. We will examine the effects of celastrol-PKM2 conjugation on PKM2 dimerization by cross-linking and molecular simulation. We will further investigate the signaling cross-talk between PKM2, HIF-1α and IL-1β. 3 To discover the in vivo effects of celastrol-PKM2 conjugation on macrophage reprogramming and adipocyte tissue remodeling in diet-induced obese mice. We postulate that in vivo celastrol-PKM2 conjugation may regulate macrophage reprogramming and adipose tissue remodeling. We will focus on three experiments: 1) Detecting covalent celastrol-PKM2 conjugate in obese mice; 2) Examining the effects of celastrol on macrophage polarization and adipose tissue remodeling; 3) Investigating the anti-obesity activity of celastrol-PKM2 conjugation.