Hepato-Vagal Nerve Pathway Switches Energy Source from Carbohydrate to Fat during Fasting

在禁食期间，哺乳动物通过从碳水化合物燃料转向脂肪燃烧来维持能量平衡。在禁食的早期阶段，肝脏从储存的糖原中动员葡萄糖。随着禁食的进行和糖原储备的消耗，脂肪组织为能量代谢提供基质。这种肝脏碳水化合物和脂肪脂质代谢的同步对正常的禁食反应至关重要。在这里，我们发现肝糖原的消耗触发了禁食期间通过肝神经元途径将能量来源从肝脏碳水化合物转换为脂肪脂质，并导致脂肪酸氧化相应增加；在长时间的禁食后，通过GYS2（糖原合成酶2）、TFE3或siPYGL（靶向糖原磷酸化酶的shRNA）腺病毒的过表达中断啮齿动物肝脏的神经信号和肝脏中糖原过载，不能完全诱导脂肪脂解。相反，siGYS2腺病毒介导的肝脏糖原消耗通过PKA（camp依赖蛋白激酶）-HSL（激素敏感脂肪酶）依赖途径促进脂肪组织的脂肪分解。这些结果表明肝糖原分解会引发肝。大脑。脂肪神经轴调节脂肪脂质燃料的动员，并在从禁食到饥饿的过程中，肝脏神经元信号在协调调节碳水化合物和脂肪酸代谢中发挥重要作用。

During fasting, mammals maintain energy balance by shifting from carbohydrate fuel to fat burning.The liver mobilizes glucose from its glycogen stores in the early stages of fasting. As fasting progresses and glycogen reserves are depleted, the adipose tissue provides substrates for energy metabolism. This synchronization of hepatic carbohydrate and adipose lipid metabolism is critical for the normal fasting response. Here, we show that depletion of liver glycogen triggers to switching the energy sources from hepatic carbohydrate to adipose lipid during fasting via hepatic neuronal pathway and causes corresponding increases in fatty acid oxidation ; Interrupting nerve signals from liver in fasting rodents and the preceding overload of glycogen in liver by the overexpression of both GYS2(glycogen synthase 2), TFE3 or siPYGL(shRNA targeting for phosphorylase glycogen liver) adenovirus fail to fully induce adipose lipolysis after a prolonged fast. Conversely, siGYS2 adenovirus-mediated glycogen depletion in liver promotes lipolysis in adipose tissue via PKA(cAMP-dependent protein kinase)-HSL(hormone-sensitive lipase) dependent pathway. These results reveal a hepatic glycogen breakdown trigger a Liver. Brain. Adipose neural axis to regulate a mobilizing adipose lipid fuel and demonstrate an important role for hepatic neuronal signal in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.