Premium
Deletion of BCATm leads to loss TORC1 signaling in response to Leu and α‐ketoisocaproate (KIC), but not insulin
Author(s) -
She Pengxiang,
Bronson Sarah K,
Vary Thomas C,
Carrel Laura,
Hutson Susan M,
Lynch Christopher J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a838
Subject(s) - p70 s6 kinase 1 , leucine , insulin , medicine , endocrinology , phosphorylation , mtorc1 , insulin receptor , signal transduction , pi3k/akt/mtor pathway , mechanistic target of rapamycin , metabolism , biology , chemistry , microbiology and biotechnology , biochemistry , amino acid , insulin resistance
Insulin and Leu stimulate a rapamycin sensitive cell‐signaling pathway involving TOR complex 1 (TORC1). While the steps leading to insulin activation are known, it is unclear how Leu activates TORC1. It has been proposed that Leu metabolism stimulates mTOR, however this hypothesis has not been rigorously tested except with non‐specific inhibitors. To address this question, we generated a line of transgenic mice (BCATm KO) missing the first step in leucine metabolism catalyzed by the mitochondrial branched chain aminotransferase isozyme (BCATm). Muscle and heart TORC1 signaling was activated following insulin injection but not after oral leucine administration. In Langendorf perfused hearts, insulin stimulated S6K1 and 4E‐BP1 phosphorylation, whereas leucine was ineffective. To bypass the BCATm block from BCATm, hearts were perfused with the BCATm reaction product, KIC; however it too failed to stimulated S6K phosphorylation. Because BCATm KO animals have elevated plasma BCAAs, TORC1 may be desensitized to Leu; therefore fibroblasts were prepared from newborn mice. Even after five passages in Minimal Essential Media, TORC1 signaling from insulin was observed, however neither Leu nor KIC activated S6K1. BCAAs concentrations were not elevated in conditioned media from KO cells. The results suggest that the BCATm plays a critical role in Leu signaling to TORC1. DK053843 (CJL), DK062880 (CJL/SMH)