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Fatty acid elongase‐5 (Elovl5) regulates the mTORC2‐FoxO1 pathway in obese‐diabetic C57BL/6J mice
Author(s) -
Tripathy Sasmita,
Jump Donald B
Publication year - 2012
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.26.1_supplement.759.2
Subject(s) - foxo1 , mtorc2 , mtorc1 , phosphorylation , akt2 , pi3k/akt/mtor pathway , serine , protein kinase b , chemistry , signal transduction , microbiology and biotechnology , cancer research , biology , akt1
Elevated fatty acid elongase‐5 (Elovl5) activity in livers of high fat diet induced obese‐ diabetic C57BL/6J mice corrects fasting hyperglycemia by suppressing gluconeogenesis (GNG) through the regulation of Akt2 and FoxO1 phosphorylation status. This report examines Elovl5 regulated signaling mechanisms controlling Akt2 & FoxO1 phosphorylation. Elevated hepatic Elovl5 activity in obese‐diabetic mice and in HepG2 cells increased Akt2‐Serine 473 (an mTORC2 site) phosphorylation. Increased Akt2‐Serine 473 correlates with increased FoxO1 phosphorylation and suppressed Pck1 gene expression. In HepG2 cells, Akt inhibitor (Akt1/2i) blocked Elovl5 mediated FoxO1 phosphorylation while the PP2A inhibitor (mycrocystin‐LR) augmented FoxO1 phosphorylation. The mTORC1 and mTORC2 inhibitor (PP242), but not the mTORC1 inhibitor (rapamycin), blocked Elovl5 regulated Akt2‐Serine 473 and FoxO1 phosphorylation. In vivo, high fat diets suppressed raptor (a mTORC1 component), but induced rictor (a mTORC2 component). Induction of hepatic Elovl5 activity augmented rictor protein abundance ~2‐fold and stimulated rictor‐mTor interaction. These studies establish rictor as a target for Elovl5 mediated suppression of GNG by regulating Akt2‐Serine 473 and FoxO1 phosphorylation. Research support: NIH (DK43220) and NIFA/USDA (2009‐65200‐05846).