Ahrentløv Nadja, Kubrak Olga, Lassen Mette, Malita Alina, Koyama Takashi, Frederiksen Amalie S, Sigvardsen Casper M, John Alphy, Madsen Pernille E H, Halberg Kenneth V, Nagy Stanislav, Imig Cordelia, Richter Erik A, Texada Michael J, Rewitz Kim
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
Nat Metab. 2025 Apr 14. doi: 10.1038/s42255-025-01267-0.
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.
动物根据反映动态常量营养素需求的饥饿感来选择食物，但特定营养素食欲调节背后的激素机制仍不清楚。在这里，我们确定速激肽（Tk）是果蝇和雌性小鼠中一种对蛋白质有反应的肠道激素，受保守的环境和营养感应机制调节。蛋白质摄入会激活表达Tk的肠内分泌细胞（EEC），通过涉及雷帕霉素靶蛋白（TOR）和瞬时受体电位A1（TrpA1）的机制驱动肠道Tk的释放。在果蝇中，我们描绘了一条肠道Tk控制蛋白质摄入后选择性食欲和睡眠的途径，该途径由胰高血糖素样脂肪动激素（AKH）向神经元和脂肪组织的信号传导介导。这种机制抑制蛋白质食欲，促进糖饥饿，并调节清醒状态，使行为与营养需求相匹配。抑制对蛋白质有反应的肠道Tk可通过AKH延长寿命，揭示了营养依赖性肠道激素信号在长寿中的作用。我们的结果为理解EEC衍生的特定营养素饱腹感信号以及肠道激素在调节食物选择、睡眠和寿命中的作用提供了一个框架。
