Expression of synphilin-1 in neurons induces hyperphagia and obesity in a Drosophila model. However, the molecular pathways underlying synphilin-1-linked obesity remain unclear. Here, Drosophila models and genetic tools were used to study the synphilin-1-linked pathways in energy balance by combining molecular biology and pharmacological approaches. We found that expression of human synphilin-1 in flies increased AMP-activated kinase (AMPK) phosphorylation at Thr172 compared with that in non-transgenic flies. Knockdown of AMPK reduced AMPK phosphorylation and food intake in non-transgenic flies, and further suppressed synphilin-1-induced AMPK phosphorylation, hyperphagia, fat storage and body weight gain in transgenic flies. Expression of constitutively activated AMPK significantly increased food intake and body weight gain in non-transgenic flies, but it did not alter food intake in the synphilin-1 transgenic flies. In contrast, expression of dominant-negative AMPK reduced food intake in both non-transgenic and synphilin-1 transgenic flies. Treatment with STO-609 also suppressed synphilin-1-induced AMPK phosphorylation, hyperphagia and body weight gain. These results demonstrate that the AMPK signaling pathway plays a critical role in synphilin-1-induced hyperphagia and obesity. These findings provide new insights into the mechanisms of synphilin-1-controlled energy homeostasis.

Synphilin-1 在神经元中的表达会在果蝇模型中诱导食欲亢进和肥胖。然而，synphilin-1 相关肥胖的分子途径仍不清楚。在这里，果蝇模型和遗传工具被用来通过结合分子生物学和药理学方法来研究能量平衡中的 synphilin-1 相关途径。我们发现，与非转基因果蝇相比，果蝇中人类 synphilin-1 的表达增加了 Thr172 的 AMP 激活激酶 (AMPK) 磷酸化。AMPK的敲低降低了非转基因果蝇中 AMPK 磷酸化和食物摄入量，并进一步抑制了转基因果蝇中 synphilin-1 诱导的 AMPK 磷酸化、食欲亢进、脂肪储存和体重增加。组成型激活的 AMPK 的表达显着增加了非转基因果蝇的食物摄入量和体重增加，但它没有改变 synphilin-1 转基因果蝇的食物摄入量。相反，显性失活 AMPK 的表达减少了非转基因果蝇和 synphilin-1 转基因果蝇的食物摄入量。STO-609 治疗还抑制了 synphilin-1 诱导的 AMPK 磷酸化、食欲亢进和体重增加。这些结果表明 AMPK 信号通路在 synphilin-1 诱导的食欲亢进和肥胖中发挥着关键作用。这些发现为synphilin-1控制的能量稳态机制提供了新的见解。