title: Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism.
abstract: Recent studies have implicated endoplasmic reticulum (ER) stress in insulin resistance associated with caloric excess. In mice placed on a 3-day high fat diet, we find augmented eIF2α signaling, together with hepatic lipid accumulation and insulin resistance. To clarify the role of the liver ER stress-dependent phospho-eIF2α (eIF2α-P) pathway in response to acute caloric excess on liver and muscle glucose and lipid metabolism, we studied transgenic mice in which the hepatic ER stress-dependent eIF2α-P pathway was inhibited by overexpressing a constitutively active C-terminal fragment of GADD34/PPP1R15a, a regulatory subunit of phosphatase that terminates ER stress signaling by phospho-eIF2α. Inhibition of the eIF2α-P signaling in liver led to a decrease in hepatic glucose production in the basal and clamped state, which could be attributed to reduced gluconeogenic gene expression, resulting in reduced basal plasma glucose concentrations. Surprisingly, hepatic eIF2α inhibition also impaired insulin-stimulated muscle and adipose tissue insulin sensitivity. This latter effect could be attributed at least in part by an increase in circulating IGFBP-3 levels in the transgenic animals. In addition, infusion of insulin during a hyperinsulinemic-euglycemic clamp induced conspicuous ER stress in the 3-day high fat diet-fed mice, which was aggravated through continuous dephosphorylation of eIF2α. Together, these data imply that the hepatic ER stress eIF2α signaling pathway affects hepatic glucose production without altering hepatic insulin sensitivity. Moreover, hepatic ER stress-dependent eIF2α-P signaling is implicated in an unanticipated cross-talk between the liver and peripheral organs to influence insulin sensitivity, probably via IGFBP-3. Finally, eIF2α is crucial for proper resolution of insulin-induced ER stress.
authors.affiliation: Howard Hughes Medical Institute and the Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Sachin
authors.initials: S
authors.lastname: Majumdar
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Joao Paulo
authors.initials: JP
authors.lastname: Camporez
authors.forename: Francois R
authors.initials: FR
authors.lastname: Jornayvaz
authors.forename: David W
authors.initials: DW
authors.lastname: Frederick
authors.forename: Blas
authors.initials: B
authors.lastname: Guigni
authors.forename: Mario
authors.initials: M
authors.lastname: Kahn
authors.forename: Dongyang
authors.initials: D
authors.lastname: Zhang
authors.forename: Dirk
authors.initials: D
authors.lastname: Weismann
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Arafat
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Pfeiffer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lieske
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; D005947:Glucose