Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice
Takashi Nomiyama, Diego Perez-Tilve, Daisuke Ogawa, Florence Gizard, Yue Zhao, Elizabeth B. Heywood, Karrie L. Jones, Ryuzo Kawamori, Lisa A. Cassis, Matthias H. Tschöp, Dennis Bruemmer
Takashi Nomiyama, Diego Perez-Tilve, Daisuke Ogawa, Florence Gizard, Yue Zhao, Elizabeth B. Heywood, Karrie L. Jones, Ryuzo Kawamori, Lisa A. Cassis, Matthias H. Tschöp, Dennis Bruemmer
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Research Article Metabolism

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

Takashi Nomiyama, Diego Perez-Tilve, Daisuke Ogawa, Florence Gizard, Yue Zhao, Elizabeth B. Heywood, Karrie L. Jones, Ryuzo Kawamori, Lisa A. Cassis, Matthias H. Tschöp, Dennis Bruemmer

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Figure 5

Chemotaxis of macrophages isolated from OPN+/+ and OPN–/– mice.

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Chemotaxis of macrophages isolated from OPN+/+ and OPN–/– mice. ...
(A) Peritoneal macrophages from OPN+/+ and OPN–/– mice were subjected to chemotaxis assays in modified Boyden chambers. Membranes of the transwell chambers were coated either with the substrate poly-D-lysine (PDL) as control or with recombinant OPN (5 ng/ml). Following attachment of the macrophages to the membrane, vehicle or MCP-1 (50 ng/ml) was added to the media in the lower chamber. Transwell migration was analyzed after 2 hours and expressed as cell numbers per HPF (×200). Experiments were repeated 4 times in triplicate. Data are expressed as mean ± SEM. *P < 0.05 compared with PDL alone; #P < 0.05 compared with OPN alone; ΧP < 0.05 compared with OPN+/+. (B) Stromal vascular cells were isolated from epididymal adipose tissues harvested from OPN+/+ (black bars) and OPN–/– (white bars) mice fed a LFD or HFD for 25 weeks (n = 6/group). Cells were cultured in the bottom chambers, and peritoneal macrophages from wild-type mice were added to the insert. Migration was analyzed in triplicate after 2 hours as described in A. Data are expressed as mean ± SEM. †P < 0.05, compared with LFD; ‡P < 0.05, compared with OPN+/+ mice fed HFD.