AUTHOR=Lv Yuqian , Lv Xiaoyan , Feng Jianshu , Cheng Fanghui , Yu Zhiyi , Guan Fengying , Chen Li 

TITLE=(20R)-panaxadiol improves obesity by promoting white fat beigeing

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1071516

DOI=10.3389/fphar.2023.1071516

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Obesity is an important cause of a range of metabolic diseases. However, the complex mechanisms of obesity and its related diseases make some weight loss methods ineffective or have safety issues. Ginseng, a specialty of Jilin Province in China with both edible and medicinal value, contains mainly ginsenosides and other components. In order to study the anti-obesity effect of ginseng, network pharmacology was used to predict and screen the active ingredients, action targets and signaling pathways of ginseng. We found (20R)-panaxadiol (PD) is a more desirable active ingredient due to its high drug-like properties and high bioavailability. Moreover, it is closely related to cAMP pathway which is more important in metabolism regulation. The corresponding pharmacodynamic targets of PD include ADRB2 (the gene encoding the β<sub>2</sub>-adrenoceptor receptor). Our study aimed to investigate whether Panaxadiol can promote white adipocyte beigeing and increase thermogenesis through modulating the β<sub>2</sub>/cAMP pathway to exert anti-obesity effects.</p><p><bold>Methods:</bold><italic>In vivo</italic>, we established high-fat feeding obesity model, genotypically obese mice (ob/ob) model, and administered PD (10 mg/kg). PD treatment in ob/ob mice along with β<sub>2</sub> receptor inhibitor ICI118551. <italic>In vitro</italic>, differentiated mature 3T3-L1 cells were given palmitate (PA) to induce hypertrophy model along with PD (20 μM).</p><p><bold>Results:</bold> The results of this study demonstrated that PD significantly reduced body weight, improved glucose tolerance and lipid levels in high-fat-induced obese mice and ob/ob mice, and also reduced lipid droplet size in PA-treated hypertrophic adipocytes <italic>in vitro</italic>. Molecular biology assays confirmed that cAMP response element binding protein (CREB) phosphorylation was increased after PD administration, and the expression of thermogenesis-related proteins UCP1, PRDM16 and mitochondrial biosynthesis-related proteins PGC-1α, TFAM and NRF1 were increased. Molecular docking results showed a low binding energy between β<sub>2</sub> receptors and PD, indicating an affinity between the β<sub>2</sub> receptor and PD. In addition, the β<sub>2</sub> receptor inhibition, reversed the anti-obesity effect of PD on the body weight, lipid droplets, the expression of thermogenesis-related proteins and CREB phosphorylation in ob/ob mice.</p><p><bold>Discussion:</bold> These results suggest that PD may promote the expression of thermogenic proteins through phosphorylation of CREB <italic>via</italic> β2 receptor activation, and thus exert anti-obesity effects.</p>