Ahrentløv, N., Kubrak, O., Lassen, M., Malita, A., Koyama, T., Frederiksen, A.S., Sigvardsen, C.M., John, A., Madsen, P.E.H., Halberg, K.V., Nagy, S., Imig, C., Richter, E.A., Texada, M.J., Rewitz, K. (2025). Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan.  Nat Metab 7(6): 1223--1245.

FBrf0262757

Research paper

Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. Here, we identify tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, we delineate a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. Our results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan.

PMC12198013 (PMC) (EuropePMC)