Circulating amino acid concentrations are defended within narrow limits, yet how the organism maintains amino acid homeostasis in the face of variable dietary protein intake remains poorly understood. We propose that, much as it does for glucose, the brain acts as a central regulator of organismal amino acid balance—continuously monitoring protein and amino acid availability and orchestrating the behavioural and peripheral metabolic responses needed to preserve it.

As a molecular entry point into this framework, we identify the low-voltage-activated calcium channel Cav3.1 in hypothalamic POMC neurons as a sensor of the essential amino acid leucine. Postprandial leucine activates mediobasal hypothalamic Cav3.1 to suppress appetite and drive weight loss in response to dietary protein, and its pharmacological activation with SAK3 promotes weight loss and potentiates GLP-1 receptor agonism in diet-induced obesity. Beyond feeding, hypothalamic Cav3.1 signalling coordinates hepatic amino acid metabolism through parasympathetic innervation: loss of this signal—by MBH Cav3.1 deletion or hepatic cholinergic denervation—locks the liver in a fasting-like program and induces FGF21 independently of the hepatocyte integrated stress response, reproducing the full behavioural and metabolic signature of protein restriction even on a protein-adequate diet.

Together, these findings define a brain-to-liver axis in which hypothalamic leucine sensing gates whole-body amino acid handling, positioning central amino acid sensing as a tractable target for obesity and metabolic disease.