Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine.
Level 5 - mechanism / opinion, no new human data
Animal research and mechanistic laboratory model (mouse knockout study)
PubMed 35771919 · doi:10.1126/science.abi9547
What was done
Investigated the physiological role of Sestrin-mediated leucine sensing in mammals using mouse models lacking Sestrin1 and Sestrin2 subjected to dietary leucine deprivation. The authors evaluated downstream mTORC1 activity, changes in white adipose tissue (WAT) and muscle mass, hepatic fibroblast growth factor 21 (FGF21) expression, and the spatial distribution of Sestrins across the liver lobule.
What was found
Mice lacking Sestrin1 and Sestrin2 failed to suppress mTORC1 signaling upon dietary leucine deprivation and experienced rapid loss of WAT and muscle tissue. The loss of WAT was mediated by aberrant liver mTORC1 activity and elevated FGF21 production. Sestrin expression was zonated within the liver lobule, coordinating zone-specific regulation of mTORC1 and FGF21 induction by leucine. The abstract reports no exact numerical values or sample sizes.
Why it matters
This study establishes Sestrin1 and Sestrin2 as functional in vivo leucine sensors in mammals and demonstrates that nutrient sensing by mTORC1 is spatially organized across liver lobules to regulate systemic metabolic responses.
Limits
Findings are limited to mouse knockout models, and translation to human physiology remains to be established. The abstract does not report sample sizes, specific quantitative effect sizes, or confidence intervals.
Cited by
- context mTORC1 in muscle tissue has a significantly higher affinity for leucine than mTORC1 in adipose tissue or hepatocytes.