Ion transport peptide regulates energy intake, expenditure, and metabolic homeostasis in Drosophila.

In mammals, energy homeostasis is regulated by the antagonistic action of hormones insulin and glucagon. However, in contrast to the highly conserved insulin, glucagon is absent in most invertebrates. Although there are several endocrine regulators of energy expenditure and catabolism (such as the adipokinetic hormone), no single invertebrate hormone with all of the functions of glucagon has been described so far. Here, we used genetic gain- and loss-of-function experiments to show that the Drosophila gene Ion transport peptide (ITP) codes for a novel catabolic regulator that increases energy expenditure, lowers fat and glycogen reserves, and increases glucose and trehalose. Intriguingly, Ion transport peptide has additional functions reminiscent of glucagon, such as inhibition of feeding and transit of the meal throughout the digestive tract. Furthermore, Ion transport peptide interacts with the well-known signaling via the Adipokinetic hormone; Ion transport peptide promotes the pathway by stimulating Adipokinetic hormone secretion and transcription of the receptor AkhR. The genetic manipulations of Ion transport peptide on standard and Adipokinetic hormone-deficient backgrounds showed that the Adipokinetic hormone peptide mediates the hyperglycemic and hypertrehalosemic effects of Ion transport peptide, while the other metabolic functions of Ion transport peptide seem to be Adipokinetic hormone independent. In addition, Ion transport peptide is necessary for critical processes such as development, starvation-induced foraging, reproduction, and average lifespan. Altogether, our work describes a novel master regulator of fly physiology with functions closely resembling mammalian glucagon.