title: Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance.
abstract: A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and liver. To determine the role of insulin action in macrophages and monocytes in obesity-associated insulin resistance, we conditionally inactivated the insulin receptor (IR) gene in myeloid lineage cells in mice (IR(Deltamyel)-mice). While these animals exhibit unaltered glucose metabolism on a normal diet, they are protected from the development of obesity-associated insulin resistance upon high fat feeding. Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle. Furthermore, IR(Deltamyel)-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) alpha and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity. This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells. These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and in the development of obesity-associated insulin resistance.
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mauer
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Chaurasia
authors.forename: Leona
authors.initials: L
authors.lastname: Plum
authors.forename: Thomas
authors.initials: T
authors.lastname: Quast
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hampel
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kolanus
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D018482:Muscle, Skeletal / Q000276:immunology; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000276:immunology*
chemical_list: D011972:Receptor, Insulin
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