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

Yingga Wu, Baoguo Li, Li Li, Sharon E Mitchell, Cara L Green, Giuseppe D'Agostino, Guanlin Wang, Lu Wang, Min Li, Jianbo Li, Chaoqun Niu, Zengguang Jin, Anyongqi Wang, Yu Zheng, Alex Douglas, John R Speakman* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)P888-904.E6
Number of pages7
JournalCell Metabolism
Issue number5
Early online date4 Mar 2021
Publication statusPublished - 4 May 2021

Bibliographical note

The study was funded by the National Key R&D Program of China (2019YFA0801900), Chinese Academy of Sciences Strategic Program (XDB13030100), the National Natural Science Foundation of China (31570409), the 1000 Talents program, a PIFI professorial fellowship award, the KC Wong Foundation, and a Wolfson merit award to J.R.S.


  • obesity
  • mTOR signaling
  • low protein
  • energy intake
  • energy expenditure
  • hunger


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