Artepillin C Time−Dependently Alleviates Metabolic Syndrome in Obese Mice by Regulating CREB/CRTC2−BMAL1 Signaling

• Published in: Nutrients Vol. 15; no. 7; p. 1644
• Main Authors: Wang, Lei, Zhou, Lingqin, Liu, Shuai, Liu, Yaxin, Zhao, Jia, Chen, Yaqiong, Liu, Yi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.03.2023; MDPI
• Subjects: Adenoviruses; Animals; Antibodies; ARNTL Transcription Factors - genetics; brain; Care and treatment; Causes of; circadian clocks; Circadian rhythm; Circadian Rhythm - physiology; Complications and side effects; drugs; Experiments; Gene Expression Regulation; Glucose; Glycerol; Health aspects; hepatocytes; histology; Homeostasis; Insulin; insulin tolerance test; lipid metabolism; Lipids; Liver; Liver - metabolism; Metabolic syndrome; Metabolic Syndrome - drug therapy; Metabolic Syndrome - metabolism; Metabolic syndrome X; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Physiological aspects; Phytochemicals; Plasmids; Propolis; Proteins; pyruvic acid; Transcription Factors - metabolism; China; United States > US; Japan; metabolic syndrome; liver; BMAL1; artepillin C; glucose and lipid metabolism; circadian rhythm
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu15071644

Artepillin C (APC), a cAMP-response element−binding (CREB)/CREB regulated transcription coactivator 2 (CRTC2) inhibitor isolated from Brazilian green propolis, can ameliorate metabolic syndrome in obese mice. Because the sensitivity and responsiveness of the body to the drug depend on the time of day and the circadian clock alignment, the optimal administration time of APC for desired efficacy in treating metabolic syndrome remains unclear. In this study, APC (20 mg/kg) or the vehicle was intraperitoneally injected into obese mice once daily for one or three weeks. The results of the insulin tolerance test, pyruvate tolerance test, and histological and biochemical assays showed that APC could improve whole−body glucose homeostasis and decrease hepatic lipid synthesis following a circadian rhythm. Further exploration of the underlying mechanism revealed that APC may disturb the diurnal oscillations of the expression of brain and muscle ARNT−like protein (BMAL1) in primary hepatocytes and the livers of the study subjects. Moreover, APC could inhibit hepatic BMAL1 expression by blocking the CREB/CRTC2 transcription complex. BMAL1 overexpression in primary hepatocytes or the livers of db/db mice antagonized the inhibitory effect of APC on hepatic lipid metabolism. In conclusion, the chronotherapy of APC may relieve metabolic syndrome in obese mice, and the mechanism behind APC−mediated time−of−day effects on metabolic syndrome were unveiled, thereby providing a foundation for optimized APC treatment from a mechanistic perspective.