MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease.
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.
Verschuren
Lars
L
TNO-Quality of Life, BioSciences, Leiden, The Netherlands.
Kooistra
Teake
T
Bernhagen
Jürgen
J
Voshol
Peter J
PJ
Ouwens
D Margriet
DM
van Erk
Marjan
M
de Vries-van der Weij
Jitske
J
Leng
Lin
L
van Bockel
J Hajo
JH
van Dijk
Ko Willems
KW
Fingerle-Rowson
Günter
G
Bucala
Rick
R
Kleemann
Robert
R
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
D015415:Biomarkers; D008263:Macrophage Migration-Inhibitory Factors; D011973:Receptors, LDL