Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
J Cell Sci. 2021 Feb 5;134(3):jcs247742. doi: 10.1242/jcs.247742.
Expression of synphilin-1 in neurons induces hyperphagia and obesity in a model. However, the molecular pathways underlying synphilin-1-linked obesity remain unclear. Here, 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 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.
在模型中，突触核蛋白-1 在神经元中的表达会导致过度摄食和肥胖。然而，突触核蛋白-1 相关肥胖的分子途径仍不清楚。在这里，通过结合分子生物学和药理学方法，使用果蝇模型和遗传工具来研究能量平衡中的突触核蛋白-1 相关途径。我们发现，与非转基因果蝇相比，人突触核蛋白-1 在果蝇中的表达增加了 AMP 激活的蛋白激酶（AMPK）在 Thr172 处的磷酸化。降低 AMPK 的表达会减少非转基因果蝇的 AMPK 磷酸化和食物摄入，并进一步抑制转基因果蝇中突触核蛋白-1 诱导的 AMPK 磷酸化、过度摄食、脂肪储存和体重增加。组成型激活的 AMPK 的表达显著增加了非转基因果蝇的食物摄入和体重增加，但它并没有改变转基因果蝇的食物摄入。相反，显性失活的 AMPK 减少了非转基因和转基因果蝇的食物摄入。STO-609 的治疗也抑制了突触核蛋白-1 诱导的 AMPK 磷酸化、过度摄食和体重增加。这些结果表明，AMPK 信号通路在突触核蛋白-1 诱导的过度摄食和肥胖中起着关键作用。这些发现为突触核蛋白-1 控制的能量平衡的机制提供了新的见解。
