Muscle Directs Diurnal Energy Homeostasis through a Myokine-Dependent Hormone Module in Drosophila

Inter-tissue communication is critical to control organismal energy homeostasis in response to temporal changes in feeding and activity or external challenges. Muscle is emerging as a key mediator of this homeostatic control through consumption of lipids, carbohydrates, and amino acids, as well as governing systemic signaling networks. However, it remains less clear how energy substrate usage tissues, such as muscle, communicate with energy substrate storage tissues in order to adapt with diurnal changes in energy supply and demand. Using Drosophila, we show here that muscle plays a crucial physiological role in promoting systemic synthesis and accumulation of lipids in fat storage tissues, which subsequently impacts diurnal changes in circulating lipid levels. Our data reveal that the metabolic transcription factor Foxo governs expression of the cytokine unpaired 2 (Upd2) in skeletal muscle, which acts as a myokine to control glucagon-like adipokinetic hormone (AKH) secretion from specialized neuroendocrine cells. Circulating AKH levels in turn regulate lipid homeostasis in fat body/adipose and the intestine. Our data also reveal that this novel myokine-dependent hormone module is critical to maintain diurnal rhythms in circulating lipids. This tissue crosstalk provides a putative mechanism that allows muscle to integrate autonomous energy demand with systemic energy storage and turnover. Together, these findings reveal a diurnal inter-tissue signaling network between muscle and fat storage tissues that constitutes an ancestral mechanism governing systemic energy homeostasis.