title: The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammation.
abstract: Inflammation provokes significant abnormalities in host metabolism that result from the systemic release of cytokines. An early response of the host is hyperglycemia and resistance to the action of insulin, which progresses over time to increased glucose uptake in peripheral tissue. Although the cytokine TNF-alpha has been shown to exert certain catabolic effects, recent studies suggest that the metabolic actions of TNF-alpha occur by the downstream regulation of additional mediators, such as macrophage migration inhibitory factor (MIF). We investigated the glycemic responses of endotoxemic mice genetically deficient in MIF (MIF(-/-)). In contrast to wild-type mice, MIF(-/-) mice exhibit normal blood glucose and lactate responses following the administration of endotoxin, or TNF-alpha. MIF(-/-) mice also show markedly increased glucose uptake into white adipose tissue in vivo in the endotoxemic state. Treatment of adipocytes with MIF, or anti-MIF mAb, modulates insulin-mediated glucose transport and insulin receptor signal transduction; these effects include the phosphorylation of insulin receptor substrate-1, its association with the p85 regulatory subunit of PI3K, and the downstream phosphorylation of Akt. Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-alpha. These studies support an important role for MIF in host glucose metabolism during sepsis.
authors.affiliation: Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Atsumi
authors.forename: You-Ree
authors.initials: YR
authors.lastname: Cho
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Courtney
authors.initials: C
authors.lastname: McDonald
authors.forename: Tim
authors.initials: T
authors.lastname: Yu
authors.forename: Cheryl
authors.initials: C
authors.lastname: Danton
authors.forename: Eun-Gyoung
authors.initials: EG
authors.lastname: Hong
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mitchell
authors.forename: Christine
authors.initials: C
authors.lastname: Metz
authors.forename: Hirokatsu
authors.initials: H
authors.lastname: Niwa
authors.forename: Jun
authors.initials: J
authors.lastname: Takeuchi
authors.forename: Shin
authors.initials: S
authors.lastname: Onodera
authors.forename: Tomomi
authors.initials: T
authors.lastname: Umino
authors.forename: Narihito
authors.initials: N
authors.lastname: Yoshioka
authors.forename: Takao
authors.initials: T
authors.lastname: Koike
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D019446:Endotoxemia / Q000097:blood / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000502:physiology; D007329:Insulin Antagonists / Q000494:pharmacology; D007333:Insulin Resistance / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007773:Lactates / Q000097:blood; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D018836:Inflammation Mediators; D007329:Insulin Antagonists; D007773:Lactates; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse