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The tongue-brain axis mediates a hidden amino acid appetite

Wu, S.; Gan, Y.; Tang, M.; Chen, S.; Luo, P.; Tong, K.; Liu, K.; Jiang, H.; Jiang, X.; Xiao, F.; Lv, W.; Yuan, F.; Guo, F.

2026-04-21 neuroscience
10.64898/2026.04.17.719133 bioRxiv
Show abstract

Selecting a diet containing all essential amino acids (EAAs) is critical for health. Following EAA deprivation, animals can select a nutritiously complete food source; however, the underlying mechanisms in vertebrates remain unclear. In mice, we show that leucine deficiency activates hypothalamic agouti-related protein (AgRP) neurons, which project to the paraventricular thalamus (PVT) via {gamma}-aminobutyric acid and are required for EAA deficiency-induced leucine appetite in mice. Furthermore, the peripheral tongue amino acid sensor general control nonderepressive-2 (GCN2) mediates acute EAA appetite via AgRP neurons. Together, these findings identify a tongue-AgRP-PVT circuit underlying EAA appetite, which is important for the rapid and accurate selection of essential nutrients.

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