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).