Increased sucrose pellet consumption in mice with access to a protein-restricted diet, relative to mice with access to a non-restricted control diet, after prolonged (7 weeks) protein restriction

Nutritional state influences behavior adaptively to maintain energy homeostasis. For example, during fasting elevated orexigenic signals drive hunger and food seeking, whereas once feeding begins, satiety hormones and anorexigenic circuits suppress “excessive” intake. While adaptive mechanisms responsive to total energy balance are relatively well studied, less is known about how animals maintain macronutrient homeostasis. Mice on low-protein diets (typically ≤10 % kcal protein) often increase their overall consumption to obtain required levels of essential amino acids (except in the case of very low protein diets (<2.5 % kcal protein) where a counterintuitive decrease in food consumption related to impaired mTOR signaling in the hypothalamus has been observed) to obtain required levels of essential amino acids, a phenomenon termed the “protein leverage effect”. Metabolic adaptations accompany this hyperphagia namely, enhanced energy expenditure, increased insulin sensitivity, and resistance to weight gain. If given multiple diet options under acute protein restriction, animals show a selective preference for protein-rich foods, and a suppression of preference for carbohydrate-rich foods. This shift in macronutrient preference presumably helps restore protein homeostasis. However, such studies have primarily focused on relatively short phases of dietary protein restriction and therefore may miss behavioral adaptations that only emerge after prolonged protein deficiency. We therefore investigated macronutrient consumption in adult C57BL/6 mice after prolonged dietary protein restriction. Contrary to findings observed under shorter periods of protein restriction, mice subjected to prolonged dietary protein restriction exhibited a generalized increase in consummatory drive, even for carbohydrate rich foods like sucrose. Our results emphasize the need to consider diet duration when assessing the behavioral and metabolic impacts of protein restriction. As restriction persists, mice exhibit more indiscriminate consummatory behavior, possibly reflecting underlying adaptive reconfigurations in metabolic or neural pathways to protect against excessive weight loss.