Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, Nagoya, 464-8650, Japan.
Laboratory of Biochemical Pharmacology, Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, 1-1 Gakuendai, Kahoku, Ishikawa, 929-1210, Japan.
J Nat Med. 2024 Jan;78(1):169-179. doi: 10.1007/s11418-023-01755-1. Epub 2023 Nov 11.
Fibroblast growth factor 21 (FGF21) is expressed in several organs, including the liver, adipose tissue, and cardiovascular system, and plays an important role in cross-talk with other organs by binding to specific FGF receptors and their co-receptors. FGF21 represents a potential target for the treatment of obesity, type 2 diabetes mellitus, and non-alcoholic steatohepatitis (NASH). The production of FGF21 in skeletal muscle was recently suggested to be beneficial for metabolic health through its autocrine and paracrine effects. However, the regulatory mechanisms of FGF21 in skeletal muscle remain unclear. In the present study, we showed that berberine regulated FGF21 production in C2C12 myotubes in a dose-dependent manner. We also examined the effects of A-674563, a selective Akt1 inhibitor, on the berberine-mediated regulation of FGF21 expression in C2C12 myotubes. Berberine significantly increased the secretion of FGF21 in C2C12 myotubes, while A-674563 attenuated this effect. Moreover, a pre-treatment with A-674563 effectively suppressed berberine-induced increases in Bmal1 expression in C2C12 myotubes, indicating that the up-regulation of Bmal1 after the berberine treatment was dependent on Akt1. Additionally, berberine-induced increases in FGF21 secretion were significantly attenuated in C2C12 cells transfected with Bmal1 siRNA, indicating the contribution of the core clock transcription factor BMAL1 to Akt-regulated FGF21 in response to berberine. Collectively, these results indicate that berberine regulates the expression of FGF21 through the Akt1 pathway in C2C12 myotubes. Moreover, the core clock gene Bmal1 may participate in the control of the myokine FGF21. Berberine stimulated Akt1-dependent FGF21 expression in C2C12 myotubes. The up-regulation of FGF21 through the modulation of PI3K/AKT1/BMAL1 in response to berberine may be involved in the regulation of cellular function (such as Glut1 expression) by acting in an autocrine and/or paracrine manner in skeletal muscle.
成纤维细胞生长因子 21（FGF21）在多个器官中表达，包括肝脏、脂肪组织和心血管系统，并通过与特定的 FGF 受体及其共受体结合，在与其他器官的串扰中发挥重要作用。FGF21 是治疗肥胖症、2 型糖尿病和非酒精性脂肪性肝炎（NASH）的潜在靶点。最近的研究表明，成纤维细胞生长因子 21 在骨骼肌中的产生通过自分泌和旁分泌作用有益于代谢健康。然而，FGF21 在骨骼肌中的调节机制尚不清楚。在本研究中，我们表明小檗碱以剂量依赖的方式调节 C2C12 肌管中的 FGF21 产生。我们还研究了 Akt1 选择性抑制剂 A-674563 对 C2C12 肌管中小檗碱介导的 FGF21 表达调节的影响。小檗碱显著增加 C2C12 肌管中 FGF21 的分泌，而 A-674563 则减弱了这种作用。此外，A-674563 的预处理可有效抑制 C2C12 肌管中小檗碱诱导的 Bmal1 表达增加，表明 Akt1 依赖于 Bmal1 的上调。此外，在转染了 Bmal1 siRNA 的 C2C12 细胞中，小檗碱诱导的 FGF21 分泌增加明显减弱，表明核心时钟转录因子 BMAL1 对 Akt 调节的 FGF21 对小檗碱的反应有贡献。总之，这些结果表明小檗碱通过 C2C12 肌管中的 Akt1 途径调节 FGF21 的表达。此外，核心时钟基因 Bmal1 可能参与调节肌因子 FGF21。小檗碱刺激 C2C12 肌管中 Akt1 依赖性 FGF21 表达。通过调节 PI3K/AKT1/BMAL1，上调 FGF21 可能通过自分泌和/或旁分泌作用在骨骼肌中调节细胞功能（如 Glut1 表达）。
