Bioactivity-based molecular networking guided identification of
guttiferone J from Garcinia cambogia as an anti-obese candidate
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.