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Bioactivity-based molecular networking guided identification of guttiferone J from Garcinia cambogia as an anti-obese candidate
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  • Zheling Feng,
  • Cheng Chen,
  • Lu Feng,
  • Jianzhong Zhu,
  • Jiali Chen,
  • Ruohan Lou,
  • Jia Liu,
  • Yang Ye,
  • Ligen Lin
Zheling Feng
University of Macau

Corresponding Author:[email protected]

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Cheng Chen
University of Macau
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Lu Feng
Shanghai Institute of Materia Medica Chinese Academy of Sciences
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Jianzhong Zhu
University of Macau
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Jiali Chen
University of Macau
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Ruohan Lou
University of Macau
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Jia Liu
Shanghai Institute of Materia Medica Chinese Academy of Sciences
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Yang Ye
Shanghai Institute of Materia Medica Chinese Academy of Sciences
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Ligen Lin
University of Macau
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Abstract

Background and Purpose: Pharmacological intervention to induce white adipose tissue browning provides a promising anti-obese therapy. The fruits of Garcinia cambogia (Clusiaceae) have been widely applied to manage body weight. The current study aims to uncover the chemical principles responsible for the anti-obese property of the fruits of G. cambogia and investigate the underlying mechanisms. Experimental Approach: The bioactivity-based molecular networking and Oil-red O staining on 3T3-L1 and C3H10T1/2 adipocytes were applied for guided isolation. High-fat diet-induced obese mice were recruited to evaluate the anti-obese activity. Key Results: Guided by the bioactivity-based molecular networking, several polycyclic polyprenylated acylphloroglucinols were targetedly isolated from the fruits of G. cambogia with lipid lowering effect on adipocytes, including guttiferone J (GOJ), garcinol and 14-deoxygarcinol. As the most potent one, GOJ (10 µM) reduced lipid accumulation by 70% and 76% in 3T3-L1 and C3H10T1/2 adipocytes, respectively. Furthermore, GOJ (2.5‒10 µM) activated the deacetylase Sirtuin 3 (SIRT3), which, in turn, reduced the acetylation level of PPARγ coactivator-1α to boost mitochondrial biogenesis, and promoted uncoupling protein 1 expression and function to enhance thermogenesis, resulting in browning of adipocytes. In high-fat diet-induced-obese mice, GOJ (10 and 20 mg∙Kg-1) protected against adiposity, hyperlipidemia, insulin resistance and liver lipotoxicity, through boosting SIRT3-mediated browning of inguinal white adipose tissue. Conclusions and Implications: The bioactivity-based molecular networking is a promising strategy for guided isolation of bioactive molecules, and GOJ represents a new scaffold of thermogenic inducer, which might be responsible for the anti-obese property of G. cambogia.
14 Jan 2022Submitted to British Journal of Pharmacology
17 Jan 2022Submission Checks Completed
17 Jan 2022Assigned to Editor
20 Jan 2022Reviewer(s) Assigned
08 Feb 2022Review(s) Completed, Editorial Evaluation Pending
09 Feb 2022Editorial Decision: Revise Minor
15 Jun 20221st Revision Received
16 Jun 2022Submission Checks Completed
16 Jun 2022Assigned to Editor
24 Jun 2022Reviewer(s) Assigned
19 Jul 2022Review(s) Completed, Editorial Evaluation Pending
25 Jul 2022Editorial Decision: Revise Minor
28 Sep 20222nd Revision Received
03 Oct 2022Submission Checks Completed
03 Oct 2022Assigned to Editor
05 Oct 2022Reviewer(s) Assigned
17 Oct 2022Review(s) Completed, Editorial Evaluation Pending
20 Oct 2022Editorial Decision: Accept