Circadian gene expression in mouse gastrocnemius muscle after deletion of SIRT1 in SF1 neurons

Loss of synchrony between geophysical time and insulin action predisposes to metabolic diseases. Yet, the brain and peripheral pathways linking proper insulin effect to diurnal changes in light/dark and feeding/fasting inputs are poorly understood. Here, we show that insulin sensitivity of several metabolically relevant tissues fluctuates during the 24-hour period. For example, in mice insulin sensitivity of skeletal muscle, liver, and adipose tissue is lowest during the light period. Mechanistically, by performing loss- and gain-of-light-action and food-restriction experiments, we demonstrate that SIRT1 in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH) conveys photic inputs toentrain the biochemical and metabolic action of insulin in skeletal muscle. These findings uncover a critical light-SF1-neuron-skeletal-muscle axis that acts to finely tune diurnal changes in insulin sensitivity and reveal a light regulatory mechanism of skeletal muscle function. Gastrocnemius muscle was dissected from 10-week old mice with deletion of SIRT1 in SF1 neurons (Sf1-Cre; Sirt1loxP/loxP) and intact controls (Sirt1loxP/loxP) at different Zeitgebers (0, 6, 12, 18).地球物理时间与胰岛素作用的同步性丧失，会增加代谢性疾病的患病风险。然而，将正常胰岛素效应与明暗周期、进食/禁食的昼夜变化联系起来的脑内与外周通路，目前仍未得到充分阐明。本研究证实，多种代谢相关组织的胰岛素敏感性在24小时周期内呈现节律性波动。例如，在小鼠模型中，骨骼肌、肝脏与脂肪组织的胰岛素敏感性在光照期处于最低水平。从机制层面出发，本研究通过开展光照剥夺、光照激活与食物限制实验，证实：下丘脑腹内侧核（VMH）内类固醇生成因子1（SF1）神经元中的沉默信息调节因子1（SIRT1），可传递光照信号，以同步骨骼肌内胰岛素的生化与代谢效应。本研究揭示了一条关键的光照-SF1神经元-骨骼肌轴，该轴可精细调控胰岛素敏感性的昼夜节律变化，并阐明了骨骼肌功能的光照调控机制。本研究在不同授时因子（Zeitgeber，0、6、12、18时）节点，分别从10周龄的SF1神经元沉默信息调节因子1（SIRT1）敲除小鼠（Sf1-Cre; Sirt1loxP/loxP）与野生型对照小鼠（Sirt1loxP/loxP）体内分离腓肠肌。