title: MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease.
abstract: 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.
authors.affiliation: TNO-Quality of Life, BioSciences, Leiden, The Netherlands.
authors.forename: Lars
authors.initials: L
authors.lastname: Verschuren
authors.forename: Teake
authors.initials: T
authors.lastname: Kooistra
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
authors.forename: D Margriet
authors.initials: DM
authors.lastname: Ouwens
authors.forename: Marjan
authors.initials: M
authors.lastname: van Erk
authors.forename: Jitske
authors.initials: J
authors.lastname: de Vries-van der Weij
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: J Hajo
authors.initials: JH
authors.lastname: van Bockel
authors.forename: Ko Willems
authors.initials: KW
authors.lastname: van Dijk
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Rick
authors.initials: R
authors.lastname: Bucala
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
mesh_terms: D052436:Adipose Tissue, White / Q000473:pathology*; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D018149:Glucose Intolerance / Q000209:etiology; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007333:Insulin Resistance; D008099:Liver / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency
chemical_list: D015415:Biomarkers; D008263:Macrophage Migration-Inhibitory Factors; D011973:Receptors, LDL