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(Circulation Research. 2009;105:99.)
© 2009 American Heart Association, Inc.

Integrative Physiology

MIF Deficiency Reduces Chronic Inflammation in White Adipose Tissue and Impairs the Development of Insulin Resistance, Glucose Intolerance, and Associated Atherosclerotic Disease

Lars Verschuren, Teake Kooistra, Jürgen Bernhagen, Peter J. Voshol, D. Margriet Ouwens, Marjan van Erk, Jitske de Vries-van der Weij, Lin Leng, J. Hajo van Bockel, Ko Willems van Dijk, Günter Fingerle-Rowson, Rick Bucala, Robert Kleemann

From the Gaubius Laboratory (L.V., T.K., J.d.V.-v.d.W., R.K.), TNO-Quality of Life, BioSciences, Leiden, The Netherlands; Departments of Vascular Surgery (L.V., J.H.v.B., R.K.), Molecular Cell Biology (D.M.O.), Endocrinology (P.J.V.), Human Genetics (J.d.V.-v.d.W., K.W.v.D.), and Internal Medicine (J.d.V.-v.d.W., K.W.v.D.), Leiden University Medical Center, The Netherlands; Department of Biochemistry and Molecular Cell Biology (J.B.), RWTH Aachen University, Germany; Physiological Genomics (M.v.E.), TNO-Quality of Life, BioSciences, Zeist, The Netherlands; Department of Hematology and Oncology (G.F.-R.), Clinic-I for Internal Medicine, University Hospital Cologne, Germany; and Department of Medicine and Pathology (L.L., R.B.), School of Medicine, Yale University, New Haven, Conn.

Correspondence to Robert Kleemann, PhD, TNO-BioSciences, Zernikedreef 9, 2301 CE Leiden, The Netherlands. E-mail Robert.Kleemann{at}tno.nl

Chronic inflammation in white adipose tissue (WAT) is positively associated with obesity, insulin resistance (IR) and the development of type 2 diabetes. The proinflammatory cytokine MIF (macrophage migration inhibitory factor) is an essential, upstream component of the inflammatory cascade. This study examines whether MIF is required for the development of obesity, IR, glucose intolerance, and atherosclerosis in the LDL receptor-deficient (Ldlr^–/–) mouse model of disease. Ldlr^–/– mice develop IR and glucose intolerance within 15 weeks, whereas Mif^–/–Ldlr^–/– littermates are protected. MIF deficiency does not affect obesity and lipid risk factors but specifically reduces inflammation in WAT and liver, as reflected by lower plasma serum amyloid A and fibrinogen levels at baseline and under inflammatory conditions. Conversely, MIF stimulates the in vivo expression of human C-reactive protein, an inflammation marker and risk factor of IR and cardiovascular disease. In WAT, MIF deficiency reduces nuclear c-Jun levels and improves insulin sensitivity; MIF deficiency also reduces macrophage accumulation in WAT and blunts the expression of two proteins that regulate macrophage infiltration (intercellular adhesion molecule-1, CD44). Mechanistic parallels to WAT were observed in aorta, where the absence of MIF reduces monocyte adhesion, macrophage lesion content, and atherosclerotic lesion size. These data highlight the physiological importance of chronic inflammation in development of IR and atherosclerosis and suggest that MIF is a potential therapeutic target for reducing the inflammatory component of metabolic and cardiovascular disorders.

Key Words: inflammation • cytokines • atherosclerosis • insulin resistance • C-reactive protein