Brain amino acid sensing for organismal amino acid homeostasis

Amino acids are essential for normal physiological functions, and disruptions in their circulating concentrations are implicated in the pathophysiology of various diseases. Therefore, understanding the mechanisms that regulate circulating amino acid levels in normal physiology is of critical importance. Evidence indicates that in healthy mammals, post-absorptive circulating levels of essential amino acids are maintained within a range that varies little from day to day or following bidirectional changes in dietary protein intake. This suggests the presence of homeostatic control mechanisms. Here, we propose a conceptual framework for the homeostatic regulation of essential amino acid availability, emphasizing the role of the brain in generating feedback controls to restore baseline levels acutely after a meal and during chronic changes in dietary protein intake. We review current evidence supporting brain amino acid sensing as a component of this regulatory system, integrating peripheral and central signals to modulate dietary protein intake and peripheral amino acid metabolism. We highlight major knowledge gaps regarding the specific neural circuits, molecular mechanisms and physiological outcomes of brain amino acid sensing. Future inquiry using the proposed framework and addressing these gaps will significantly enhance our understanding of the pathways involved in the maintenance of circulating amino acid availability and the regulation of lean mass in health, disease states or in response to therapeutic strategies for metabolic diseases.