Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine

• DOI: 10.1126/science.abi9547
• Publication Date: 2022-06-30T17:59:06Z
• Authors: Andrew L. Cangelosi; Anna M. Puszynska; Justin M. Roberts; Andrea Armani; Thao P. Nguyen; Jessica B. Spinelli; Tenzin Kunchok; Brianna Wang; Sze Ham Chan; Caroline A. Lewis; William C. Comb; George W. Bell; Aharon Helman; David M. Sabatini
• Keywords: FGF21

The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through leucine-binding Sestrin proteins, but physiological functions and distribution Sestrin-mediated sensing mammals are unknown. We find that mice lacking Sestrin1 Sestrin2 cannot inhibit upon dietary deprivation suffer a rapid loss white adipose tissue (WAT) muscle. WAT is driven by aberrant activity fibroblast factor 21 (FGF21) production liver. expression liver lobule zonated, accounting for zone-specific regulation FGF21 induction These results establish mammalian Sestrins as sensors reveal spatial organization nutrient pathway.