title: Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice.
abstract: To understand the physiological significance of the reduction in fasting insulin produced by dietary methionine restriction (MR), hyperinsulinemic-euglycemic clamps were used to examine the effect of the diet on overall and tissue-specific insulin sensitivity in mice. The steady-state glucose infusion rate was threefold higher in the MR group and consistent with the 2.5- to threefold increase in 2-deoxyglucose uptake in skeletal muscle, heart, and white adipose tissue. Dietary MR enhanced suppression of hepatic glucose production by insulin, enhanced insulin-dependent Akt phosphorylation in the liver, and increased hepatic expression and circulating fibroblast growth factor 21 (FGF-21) by fourfold. Limitation of media methionine recapitulated amplification of Akt phosphorylation by insulin in HepG2 cells but not in 3T3-L1 adipocytes or C2C12 myotubes. Amplification of insulin signaling in HepG2 cells by MR was associated with reduced glutathione, where it functions as a cofactor for phosphatase and tensin homolog. In contrast, FGF-21, but not restricting media methionine, enhanced insulin-dependent Akt phosphorylation in 3T3-L1 adipocytes. These findings provide a potential mechanism for the diet-induced increase in insulin sensitivity among tissues that involves a direct effect of methionine in liver and an indirect effect in adipose tissue through MR-dependent increases in hepatic transcription and release of FGF-21.
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Kirsten P
authors.initials: KP
authors.lastname: Stone
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Desiree
authors.initials: D
authors.lastname: Wanders
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Manda
authors.initials: M
authors.lastname: Orgeron
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Cory C
authors.initials: CC
authors.lastname: Cortez
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA gettystw@pbrc.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gettys
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D003847:Deoxyglucose; D008715:Methionine; D051057:Proto-Oncogene Proteins c-akt