Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis.

Baumgartl J, Baudler S, Scherner M, Babaev V, Makowski L, Suttles J, McDuffie M, Tobe K, Kadowaki T, Fazio S, Kahn CR, Hotamisligil GS, Krone W, Linton M, BrĂ¼ning JC
Cell Metab. 2006 3 (4): 247-56

PMID: 16581002 · PMCID: PMC4027059 · DOI:10.1016/j.cmet.2006.02.010

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-1beta 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.

MeSH Terms (19)

Adoptive Transfer Animals Apolipoproteins E Atherosclerosis Blotting, Western Cell Line Cell Lineage Immunoprecipitation Insulin Insulin Resistance Interleukin-1 Interleukin-6 Macrophages Mice Mice, Inbred C57BL Mice, Knockout Myeloid Cells Receptor, Insulin Signal Transduction

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