2. Academic Validation
  3. Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

  • Diabetologia. 2016 Jun;59(6):1276-86. doi: 10.1007/s00125-016-3912-9.
Li Feng 1 2,  Huan Luo 3,  Zhijian Xu 4,  Zhuo Yang 4,  Guoxin Du 1,  Yu Zhang 2,  Lijing Yu 2,  Kaifeng Hu 3,  Weiliang Zhu 4,  Qingchun Tong 5,  Kaixian Chen 1 4,  Fujiang Guo 6,  Cheng Huang 7,  Yiming Li 8
Affiliations

Affiliations

  • 1 Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.
  • 2 Laboratory of Drug Discovery, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.
  • 3 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China.
  • 4 CAS Key Laboratory for Membrane Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
  • 5 The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 6 Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. gfj@shutcm.edu.cn.
  • 7 Laboratory of Drug Discovery, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. chuang@shutcm.edu.cn.
  • 8 Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. ymli@shutcm.edu.cn.
PMID: 26983922 DOI: 10.1007/s00125-016-3912-9
Abstract

Aims/hypothesis: Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome.

Methods: Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies.

Results: BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site.

Conclusions/interpretation: This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.

Keywords

Alternative binding site; Bavachinin; Canonical ligand-binding pocket; Carbohydrate metabolism; Lipid metabolism; Pan-PPAR agonist; Synergistic effects.

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