TY - JOUR
T1 - Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis
AU - Baumgartl, Julia
AU - Baudler, Stephanie
AU - Scherner, Maximilian
AU - Babaev, Vladimir
AU - Makowski, Liza
AU - Suttles, Jill
AU - McDuffie, Marcia
AU - Fazio, Sergio
AU - Kahn, C. Ronald
AU - Hotamisligil, Gökhan S.
AU - Krone, Wilhelm
AU - Linton, MacRae
AU - Brüning, Jens C.
N1 - Funding Information:
We wish to thank Takashi Kadowaki for providing IRS-2-deficient mice. We are grateful to Gisela Schmall for excellent secretarial assistance, to Frank Edenhofer for kindly providing the recombinant HNTC protein, and to Irmgard Förster for providing the LysM-Cre-transgenic mice. The study was supported by funds of the Center of Molecular Medicine Cologne (CMMC to J.C.B. and W.K.), the Deutsch Forschungsgemeinschaft (DFG) (1492-3/1 to J.C.B.), and the National Institutes of Health (NIH) (NRSA F32 HL075970-01 to L.M.).
PY - 2006/4
Y1 - 2006/4
N2 - Inflammatory processes play an important role in the pathogenesis of vascular diseases, and insulin-resistant diabetes mellitus type 2 represents an important risk factor for the development of atherosclerosis. To directly address the role of insulin resistance in myeloid lineage cells in the development of atherosclerosis, we have created mice with myeloid lineage-specific inactivation of the insulin receptor gene. On an ApoE-deficient background, MphIRKO mice developed smaller atherosclerotic lesions. There was a dramatic decrease in LPS-stimulated IL-6 and IL-1β expression in the presence of macrophage autonomous insulin resistance. Consistently, while insulin-resistant IRS-2-deficient mice on an ApoE-deficient background display aggravated atherosclerosis, fetal liver cell transplantation of IRS-2-/-ApoE-/- cells ameliorated atherosclerosis in Apo-E-deficient mice. Thus, systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis, providing direct evidence that myeloid lineage autonomous insulin signaling provides proinflammatory signals predisposing to the development of atherosclerosis.
AB - Inflammatory processes play an important role in the pathogenesis of vascular diseases, and insulin-resistant diabetes mellitus type 2 represents an important risk factor for the development of atherosclerosis. To directly address the role of insulin resistance in myeloid lineage cells in the development of atherosclerosis, we have created mice with myeloid lineage-specific inactivation of the insulin receptor gene. On an ApoE-deficient background, MphIRKO mice developed smaller atherosclerotic lesions. There was a dramatic decrease in LPS-stimulated IL-6 and IL-1β expression in the presence of macrophage autonomous insulin resistance. Consistently, while insulin-resistant IRS-2-deficient mice on an ApoE-deficient background display aggravated atherosclerosis, fetal liver cell transplantation of IRS-2-/-ApoE-/- cells ameliorated atherosclerosis in Apo-E-deficient mice. Thus, systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis, providing direct evidence that myeloid lineage autonomous insulin signaling provides proinflammatory signals predisposing to the development of atherosclerosis.
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U2 - 10.1016/j.cmet.2006.02.010
DO - 10.1016/j.cmet.2006.02.010
M3 - Article
C2 - 16581002
AN - SCOPUS:33645563765
SN - 1550-4131
VL - 3
SP - 247
EP - 256
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -