title: FGF21 suppresses hepatic glucose production through the activation of atypical protein kinase Cι/λ.
abstract: Fibroblast growth factor 21 (FGF21) has been identified as a potent and robust metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys exerts strong anti-diabetic effects. Previous studies have demonstrated that FGF21 inhibits glucose output in the rat H4IIE hepatoma cell line. We performed pharmacological studies to investigate the mechanisms by which FGF21 regulates glucose production in these cells. We found that both insulin and FGF21 suppressed gene expression of G6Pase and PEPCK. Accordingly, glucose production was inhibited. The FGF21 effects were phosphoinositide 3-kinase (PI3K)-dependent, and, unlike insulin, Akt-independent. Additionally, we found that FGF21 induced PKCι/λ phosphorylation in a PI3K-dependent manner; and that a non-isoform selective PKC inhibitor blocked FGF21 inhibition of glucose production, while an inhibitor of classical and novel PKC isoforms had no effect on FGF21 inhibitory activity. Furthermore, hepatic PKCι/λ phosphorylation was upregulated in FGF21-treated diabetic db/db mice.These data support the proposition that FGF21 inhibits hepatic glucose production by the PI3K-dependent activation of PKCι/λ.
authors.affiliation: Merck Research Laboratories, RY80T-B119, Rahway, NJ 07065, USA. ling-jie_kong@merck.com
authors.forename: Ling-Jie
authors.initials: LJ
authors.lastname: Kong
authors.forename: Wen
authors.initials: W
authors.lastname: Feng
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.forename: Yuli
authors.initials: Y
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Dallas-yang
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D000099293:Protein Kinase C-lambda
chemical_list: D005346:Fibroblast Growth Factors; D005947:Glucose; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; C414620:fibroblast growth factor 21