title: Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice.
abstract: Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. During immune responses, tissue infiltration by macrophages is dependent on the expression of osteopontin, an extracellular matrix protein and proinflammatory cytokine that promotes monocyte chemotaxis and cell motility. In the present study, we used a murine model of diet-induced obesity to examine the role of osteopontin in the accumulation of adipose tissue macrophages and the development of insulin resistance during obesity. Mice exposed to a high-fat diet exhibited increased plasma osteopontin levels, with elevated expression in macrophages recruited into adipose tissue. Obese mice lacking osteopontin displayed improved insulin sensitivity in the absence of an effect on diet-induced obesity, body composition, or energy expenditure. These mice further demonstrated decreased macrophage infiltration into adipose tissue, which may reflect both impaired macrophage motility and attenuated monocyte recruitment by stromal vascular cells. Finally, obese osteopontin-deficient mice exhibited decreased markers of inflammation, both in adipose tissue and systemically. Taken together, these results suggest that osteopontin may play a key role in linking obesity to the development of insulin resistance by promoting inflammation and the accumulation of macrophages in adipose tissue.
authors.affiliation: Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomiyama
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Florence
authors.initials: F
authors.lastname: Gizard
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.forename: Karrie L
authors.initials: KL
authors.lastname: Jones
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Kawamori
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
mesh_terms: D000273:Adipose Tissue / Q000276:immunology*; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007333:Insulin Resistance / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity / Q000150:complications / Q000276:immunology*; D053495:Osteopontin / Q000235:genetics / Q000502:physiology*