Homeostatic regulation of protein intake: in search of a mechanism

Abstract

Free-living organisms must procure adequate nutrition by negotiating an environment in which both the quality and quantity of food vary markedly. Recent decades have seen marked progress in our understanding of neural regulation of feeding behavior. However, this progress has occurred largely in the context of energy intake, despite the fact that food intake is influenced by more than just the energy content of the diet. A large number of behavioral studies indicate that both the quantity and quality of dietary protein can markedly influence food intake. High-protein diets tend to reduce intake, low-protein diets tend to increase intake, and rodent models seem to self-select between diets in order to meet protein requirements and avoid diets that are imbalanced in amino acids. Recent work suggests that the amino acid leucine regulates food intake by altering mTOR and AMPK signaling in the hypothalamus, while activation of GCN2 within the anterior piriform cortex contributes to the detection and avoidance of amino acid-imbalanced diets. This review focuses on the role that these and other signaling systems may play in mediating the homeostatic regulation of protein balance, and in doing so, highlights our lack of knowledge regarding the physiological and neurobiological mechanisms that might underpin such a regulatory phenomenon.

Fig. 1.

Regulation of protein intake and selection. Foods containing dietary protein generate exteroceptive cues (e.g., taste and smell), resulting in learned associations between the sensory properties of the food and the postingestive consequences of its consumption. Interoceptive cues related to dietary protein content (gastrointestinal tract and liver) and protein stores/amino acid metabolism (muscle and liver) converge on the central nervous system, although the specific nature of these signals remains unclear. Cues of protein status are likely integrated within areas of the anterior piriform cortex (APC), hypothalamus, and/or brain stem, collectively serving to detect protein deficiency or imbalance. Cortico-limbic reward circuitry interacts with prior food memories to influence selection based on need state. In other words, protein depletion generates a need state signal, such that high-protein foods and the memories associated with those foods become increasingly salient and thus preferred. OFC, orbitofrontal cortex; Hipp, hippocampus; Amy, amygdala; VTA, ventral tegmental area; NAcb, nucleus accumbens.