Objective

Salt-induced kinase 1 (SIK1) acts as a key modulator in many physiological processes. However, the effects of SIK1 on gluconeogenesis and the underlying mechanisms have not been fully elucidated. In this study, we found that a natural compound phanginin A could activate SIK1 and further inhibit gluconeogenesis. The mechanisms by which phanginin A activates SIK1 and inhibits gluconeogenesis were explored in primary mouse hepatocytes, and the effects of phanginin A on glucose homeostasis were investigated in ob/ob mice.

Methods

The effects of phanginin A on gluconeogenesis and SIK1 phosphorylation were examined in primary mouse hepatocytes. Pan-SIK inhibitor and siRNA-mediated knockdown were used to elucidate the involvement of SIK1 activation in phanginin A-reduced gluconeogenesis. LKB1 knockdown was used to explore how phanginin A activated SIK1. SIK1 overexpression was used to evaluate its effect on gluconeogenesis, PDE4 activity, and the cAMP pathway. The acute and chronic effects of phanginin A on metabolic abnormalities were observed in ob/ob mice.

Results

Phanginin A significantly increased SIK1 phosphorylation through LKB1 and further suppressed gluconeogenesis by increasing PDE4 activity and inhibiting the cAMP/PKA/CREB pathway in primary mouse hepatocytes, and this effect was blocked by pan-SIK inhibitor HG-9-91-01 or siRNA-mediated knockdown of SIK1. Overexpression of SIK1 in hepatocytes increased PDE4 activity, reduced cAMP accumulation, and thereby inhibited gluconeogenesis. Acute treatment with phanginin A reduced gluconeogenesis in vivo, accompanied by increased SIK1 phosphorylation and PDE4 activity in the liver. Long-term treatment of phanginin A profoundly reduced blood glucose levels and improved glucose tolerance and dyslipidemia in ob/ob mice.

Conclusion

We discovered an unrecognized effect of phanginin A in suppressing hepatic gluconeogenesis and revealed a novel mechanism that activation of SIK1 by phanginin A could inhibit gluconeogenesis by increasing PDE4 activity and suppressing the cAMP/PKA/CREB pathway in the liver. We also highlighted the potential value of phanginin A as a lead compound for treating type 2 diabetes.

中文翻译：

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phanginin A 激活 SIK1 通过增加 PDE4 活性和抑制 cAMP 信号通路来抑制肝脏糖异生。

客观的

盐诱导激酶 1 (SIK1) 在许多生理过程中充当关键调节剂。然而，SIK1对糖异生的影响及其潜在机制尚未完全阐明。在这项研究中，我们发现天然化合物 phanginin A 可以激活 SIK1 并进一步抑制糖异生。在原代小鼠肝细胞中探索了 phanginin A 激活 SIK1 并抑制糖异生的机制，并在ob/ob小鼠中研究了 phanginin A 对葡萄糖稳态的影响。

方法

在原代小鼠肝细胞中检查了 phanginin A 对糖异生和 SIK1 磷酸化的影响。Pan-SIK 抑制剂和 siRNA 介导的敲低被用来阐明 SIK1 激活参与 phanginin A 减少的糖异生。LKB1 敲低用于探索 phanginin A 如何激活 SIK1。SIK1 过表达用于评估其对糖异生、PDE4 活性和 cAMP 途径的影响。在ob/ob小鼠中观察到 phanginin A 对代谢异常的急性和慢性影响。

结果

Phanginin A 通过 LKB1 显着增加 SIK1 磷酸化，并通过增加 PDE4 活性和抑制原代小鼠肝细胞中的 cAMP/PKA/CREB ​​通路进一步抑制糖异生，这种作用被 pan-SIK 抑制剂 HG-9-91-01 或 siRNA-阻断介导的 SIK1 敲低。SIK1 在肝细胞中的过表达增加了 PDE4 的活性，减少了 cAMP 的积累，从而抑制了糖异生。用 phanginin A 进行急性治疗会减少体内糖异生，同时增加肝脏中的 SIK1 磷酸化和 PDE4 活性。phanginin A 的长期治疗显着降低了ob/ob小鼠的血糖水平并改善了葡萄糖耐量和血脂异常。

结论

我们发现了 phanginin A 在抑制肝脏糖异生方面的一种未被认识的作用，并揭示了一种新机制，即 phanginin A 激活 SIK1 可以通过增加 PDE4 活性和抑制肝脏中的 cAMP/PKA/CREB ​​通路来抑制糖异生。我们还强调了 phanginin A 作为治疗 2 型糖尿病的先导化合物的潜在价值。