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The Journal of Immunology, 2007, 179, 5399 -5406
Copyright © 2007 by The American Association of Immunologists, Inc.
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The Proinflammatory Cytokine Macrophage Migration Inhibitory Factor Regulates Glucose Metabolism during Systemic Inflammation1

Toshiya Atsumi*, You-Ree Cho§, Lin Leng§, Courtney McDonald§, Tim Yu§, Cheryl Danton§, Eun-Gyoung Hong§, Robert A. Mitchell{dagger}, Christine Metz{ddagger}, Hirokatsu Niwa*, Jun Takeuchi*, Shin Onodera*, Tomomi Umino*, Narihito Yoshioka*, Takao Koike*, Jason K. Kim§ and Richard Bucala2,§

* Graduate School of Medicine, Hokkaido University, Sapporo, Japan; {dagger} J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202; {ddagger} North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030; § Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT 06520

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by Grants AI42310 (to R.B.), AR050498 (to R.B.), U24 DK-59635 (to J.K.K.), and ADA 1-04RA-47 (to J.K.K.) from the National Institutes of Health.

2 Address correspondence and reprint requests to Dr. Richard Bucala, Departments of Medicine, Pathology, and Epidemiology and Public Health, The Anlyan Center, S525, P.O. Box 208031, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520. E-mail address: Richard.Bucala{at}Yale.edu

3 Abbreviations used in this paper: MIF, macrophage migration inhibitory factor; IRS-1, insulin receptor substrate 1; MEF, murine embryonic fibroblast; PPAR, peroxisome proliferator-activated receptor; 2-[14C]DG, 2-deoxy-D-[1-14C]glucose; WT, wild type.




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