The regulation of circadian rhythm by insulin signaling in Drosophila

Circadian rhythm is well conserved across species and relates to numerous biological functions. Circadian misalignment impairs metabolic function. Insulin signaling is a key modulator of metabolism in the fruit fly as well as mammals and its defects cause metabolic disease. Daily diet timing affects both circadian rhythmicities of behavior and metabolism. However, the relationship between circadian clock and insulin signaling is still elusive. Here, we report that insulin signaling regulates circadian rhythm in Drosophila melanogaster . We found the insulin receptor substrate mutant, chico 1 , showed a shorter free-running circadian period. The knockdown of insulin receptor ( InR ), or another signaling molecule downstream of InR, dp110 , or the expression of a dominant-negative form of InR resulted in the shortening of the circadian period and diminished its amplitude. The impairment of insulin signaling both in all neurons and restricted circadian clock neurons altered circadian period length, indicating the insulin signaling plays a role in the regulation of circadian rhythm in clock cells. Among 3 insulin-like ligands expressed in the brain, dilp5 showed the largest effect on circadian phenotype when deleted. These results suggested that insulin signaling contributes to the robustness of the circadian oscillation and coordinates metabolism and behavior. Highlights Insulin receptor substrate mutant, chico 1 , displayed circadian rhythm phenotype. Pan-neuronal inhibition of insulin receptor signaling shortened circadian cycle. Inhibition of insulin signaling only in clock neurons altered circadian cycle. Dilp5 is a major insulin receptor ligand for circadian effects.