Very-low-protein diets lead to reduced food intake and weight loss, linked to inhibition of hypothalamic mTOR signaling, in mice.

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.