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.

FGF21 is an endocrine signal of protein restriction

“…Previous experiments by our group and others demonstrate that protein restriction increases food intake in mice, rats, and humans (3,4,31,40), and WT mice in this study also increased food intake on the LP diet. The LP diet also increased EE, a previously established response to protein restriction that presumably involves activation of the sympathetic nervous system (41,42).…”

“…To determine whether FGF21 is required for adaptive responses to protein restriction, WT and Fgf21-deficient mice were placed on a LP diet for 14 days. As expected (4,31,(39)(40)(41)(42), WT mice displayed both increased food intake ( Figure 5E) and a progressive increase in EE ( Figure 5A) following the switch to LP diet. Specifically, EE increased, by approximately 15% in WT mice by days 5 to 7 (P < 0.01; Figure 5, C and D), an effect detected during both the light and dark periods.…”

“…Dietary protein intake is also critical for survival, and while several lines of evidence support the hypothesis that protein intake is regulated (1)(2)(3), little is known regarding how the body detects dietary protein restriction or engages adaptive metabolic and behavioral responses (4).…”

A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution

“…Indeed, the specific role of dietary protein in obesity and diabetes is less well understood and controversial (5). On one hand, the satiating effects of dietary protein are well established (6), and there are several studies in rodents (7,8) and even humans (9) demonstrating higher energy intake and subsequent fat mass gain with consumption of a protein-diluted diet. The phenomenon of animals modifying their caloric intake in order to meet a daily protein target was coined the "protein leverage" hypothesis by Simpson and Raubenheimer (10).…”

Leucine acts in the brain to suppress food intake but does not function as a physiological signal of low dietary protein

“…Despite these behavioral observations, the mechanism regulating protein intake is largely unknown (21). Recent work has focused on the branched-chain amino acid (BCAA) leucine as a potential protein signal.…”