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Pharmaceutics
Volume 14
Issue 6
10.3390/pharmaceutics14061192
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Article

Ginsenoside Compound K Protects against Obesity through Pharmacological Targeting of Glucocorticoid Receptor to Activate Lipophagy and Lipid Metabolism

by
Siwen Yang
1,
Ting Liu
1,
Chenxing Hu
1,
Weili Li
1,
Yuhan Meng
1,
Haiyang Li
1,
Chengcheng Song
1,
Congcong He
2,
Yifa Zhou
1,* and
Yuying Fan
1,*
1
Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
2
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
*
Authors to whom correspondence should be addressed.
Pharmaceutics 2022, 14(6), 1192; https://doi.org/10.3390/pharmaceutics14061192
Submission received: 1 April 2022 / Revised: 19 May 2022 / Accepted: 23 May 2022 / Published: 2 June 2022
(This article belongs to the Special Issue Trends in Obesity Research and Anti-Obesity Therapeutics)
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Abstract

(1) Background: The glucocorticoid receptor (GR) plays a key role in lipid metabolism, but investigations of GR activation as a potential therapeutic approach have been hampered by a lack of selective agonists. Ginsenoside compound K (CK) is natural small molecule with a steroid-like structure that offers a variety of therapeutic benefits. Our study validates CK as a novel GR agonist for the treatment of obesity. (2) Methods: By using pulldown and RNA interference, we determined that CK binds to GR. The anti-obesity potential effects of CK were investigated in obese mice, including through whole-body energy homeostasis, glucose and insulin tolerance, and biochemical and proteomic analysis. Using chromatin immunoprecipitation, we identified GR binding sites upstream of lipase ATGL. (3) Results: We demonstrated that CK reduced the weight and blood lipids of mice more significantly than the drug Orlistat. Proteomics data showed that CK up-regulated autophagy regulatory proteins, enhanced fatty acid oxidation proteins, and decreased fatty acid synthesis proteins. CK induced lipophagy with the initial formation of the phagophore via AMPK/ULK1 activation. However, a blockade of autophagy did not disturb the increase in CK on lipase expression, suggesting that autophagy and lipase are independent pathways in the function of CK. The pulldown and siRNA experiments showed that GR is the critical target. After binding to GR, CK not only activated lipophagy, but also promoted the binding of GR to the ATGL promoter. (4) Conclusions: Our findings indicate that CK is a natural food candidate for reducing fat content and weight.
Keywords: ATGL; ginsenoside CK; GR; lipophagy; lipid metabolism ATGL; ginsenoside CK; GR; lipophagy; lipid metabolism

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MDPI and ACS Style

Yang, S.; Liu, T.; Hu, C.; Li, W.; Meng, Y.; Li, H.; Song, C.; He, C.; Zhou, Y.; Fan, Y. Ginsenoside Compound K Protects against Obesity through Pharmacological Targeting of Glucocorticoid Receptor to Activate Lipophagy and Lipid Metabolism. Pharmaceutics 2022, 14, 1192. https://doi.org/10.3390/pharmaceutics14061192

AMA Style

Yang S, Liu T, Hu C, Li W, Meng Y, Li H, Song C, He C, Zhou Y, Fan Y. Ginsenoside Compound K Protects against Obesity through Pharmacological Targeting of Glucocorticoid Receptor to Activate Lipophagy and Lipid Metabolism. Pharmaceutics. 2022; 14(6):1192. https://doi.org/10.3390/pharmaceutics14061192

Chicago/Turabian Style

Yang, Siwen, Ting Liu, Chenxing Hu, Weili Li, Yuhan Meng, Haiyang Li, Chengcheng Song, Congcong He, Yifa Zhou, and Yuying Fan. 2022. "Ginsenoside Compound K Protects against Obesity through Pharmacological Targeting of Glucocorticoid Receptor to Activate Lipophagy and Lipid Metabolism" Pharmaceutics 14, no. 6: 1192. https://doi.org/10.3390/pharmaceutics14061192

APA Style

Yang, S., Liu, T., Hu, C., Li, W., Meng, Y., Li, H., Song, C., He, C., Zhou, Y., & Fan, Y. (2022). Ginsenoside Compound K Protects against Obesity through Pharmacological Targeting of Glucocorticoid Receptor to Activate Lipophagy and Lipid Metabolism. Pharmaceutics, 14(6), 1192. https://doi.org/10.3390/pharmaceutics14061192

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