Complex interplay of neuronal and hormonal gut-brain responses to essential amino acid deficit
- Boram Kim
- Seongju Lee
- Hyeyeon Bae
- Shinhye Kim
- Jong-Hoon Won
- Dongwoo Kim
- Byungkwon Jung
- Makoto I. Kanai
- Sung-Eun Yoon
- Yangkyun Oh
- Won-Jae Lee
- Greg S. B. Suh
2026-05-21
A deficit in dietary protein elicits a nutrient-specific appetite, yet the underlying mechanisms remain poorly understood. In this work, we identify coordinated neuronal and systemic mechanisms in Drosophila that drive an essential amino acid (EAA)–specific appetite. EAA deprivation increases neuropeptide CNMamide (CNMa) expression in gut enterocytes, activating enteric neurons and ellipsoid body neurons in the brain to promote EAA intake through two complementary pathways: a rapid neuronal gut-brain axis and a slower hormonal route. CNMa suppresses the activity of sugar-sensing diuretic hormone 44 (DH44) neurons, thereby reducing carbohydrate intake and biasing feeding toward EAAs. Similarly, protein deprivation in mice promotes an EAA-specific appetite independently of fibroblast growth factor 21 ( FGF21 ). Together, these findings reveal multilayered gut-brain mechanisms that regulate nutrient-specific feeding and maintain EAA homeostasis across species.