Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Nutrients. 2023 Mar 28;15(7):1644. 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 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.
阿魏酸苯乙酯（APC）是一种从巴西绿蜂胶中分离出的环磷酸腺苷反应元件结合蛋白（CREB）/CREB 调节转录共激活因子 2（CRTC2）抑制剂，可改善肥胖小鼠的代谢综合征。由于机体对药物的敏感性和反应性取决于一天中的时间和昼夜节律的调整，因此，为了达到治疗代谢综合征的理想疗效，APC 的最佳给药时间尚不清楚。在这项研究中，APC（20mg/kg）或载体通过腹腔注射每天一次给肥胖小鼠给药 1 或 3 周。胰岛素耐量试验、丙酮酸耐量试验以及组织学和生化分析的结果表明，APC 可以改善全身葡萄糖稳态，并根据昼夜节律降低肝脏脂质合成。对潜在机制的进一步探索表明，APC 可能会干扰原代肝细胞和研究对象肝脏中脑和肌肉 ARNT 样蛋白（BMAL1）的昼夜节律表达波动。此外，APC 通过阻断 CREB/CRTC2 转录复合物可以抑制肝 BMAL1 的表达。原代肝细胞或小鼠肝脏中的 BMAL1 过表达拮抗了 APC 对肝脂代谢的抑制作用。总之，APC 的时间治疗可能会缓解肥胖小鼠的代谢综合征，并且揭示了 APC 介导的代谢综合征昼夜节律作用的机制，从而从机制角度为优化 APC 治疗提供了基础。
