A nutrient-hormone axis pivots an energy trade-off between resting thermogenesis and movement expenditure

• Chronic dietary protein restriction improves weight being exercise ability in male mice • Chronic dietary protein restriction improves running economy and lowers daily physical activity energy expenditure • These effects occur though lower body weight and adiposity driven by activation brown adipose tissue thermogenesis via liver-derived fibroblast growth factor 21 • Overall, the higher thermogenesis energy expenditure is offset by lower physical activity energy expenditure • Our findings may provide a reason for the existence of diet-induced thermogenesis The biological reason why mammals increase daily energy expenditure when consuming a protein-dilute diet is currently enigmatic. Recognizing that body weight is a chief determinant of movement economy, we hypothesized that there is an interaction between dietary protein dilution-induced resting energy expenditure and subsequent effects on body weight and energy expenditure during physical activity. Using inbred and genetically modified mice and methods such as defined diet feeding, body composition analysis, indirect calorimetry combined with forced treadmill running or in-cage wheel running, tissue histological and molecular/biochemical analyses, we examined the interactions of diet and exercise biology. We found that mice chronically fed a protein-dilute diet exhibited enhanced weight-bearing exercise ability, an effect directly linked to the improved movement economy. Mechanistically, this improved movement economy and exercise ability resulted from a reduction in adiposity and body weight, which was facilitated by the increased liver-derived fibroblast growth factor 21 (FGF21) that promotion of brown adipose tissue thermogenesis. Overall, dietary protein dilution-induced thermogenesis and resulting improved movement economy enabled a differential budgeting of energy expenditure between active and inactive states, resulting in balanced total energy expenditure. The influence of liver-derived FGF21 on brown adipose tissue thermogenesis and energy expenditure drives improved movement economy and weight-bearing exercise capability during chronic dietary protein dilution.