Intracellular amino acid scarcity sensing tunes protein hunger

Abstract

Protein is a key macronutrient that strongly governs food intake. Following dietary protein scarcity, animals display compensatory preference for amino acid-rich food, yet how the brain detects and encodes protein hunger remains unclear. To address this question, we used Drosophila melanogaster to investigate the function of peptidergic neurons, a major neuromodulatory cell population that includes key regulators of feeding behaviour and protein homeostasis. We present a high-resolution transcriptional atlas obtained by RNA sequencing of single peptidergic nuclei isolated from the brains of sated and amino acid deprived flies. Consistent with a resource-sparing response, differential expression analysis revealed widespread transcriptional downregulation in the amino acid deprived state. A screen of differently expressed candidates identified Lsp2, a gene encoding an amino acid storage protein, as a regulator of protein intake. Knock down and overexpression experiments demonstrate that Lsp2 levels act as a gauge in a specific population of peptidergic neurons expressing Myoinhibiting peptide precursor (Mip) to modulate protein appetite. We further show that compensatory protein feeding following amino acid deprivation depends on maintaining Mip+ neuron activity within an appropriate range. Our findings reveal that peptidergic neurons can directly sense intracellular protein deficiency and use this information to guide protein intake. By linking amino acid storage to the neuronal control of feeding, this work establishes a foundation for understanding how protein needs are encoded in the brain.