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- Title
Blockade of α4 Integrin Signaling Ameliorates the Metabolic Consequences of High-Fat Diet--Induced Obesity.
- Authors
Féral, Chloé C.; Neels, Jaap G.; Kummer, Christiane; Slepak, Marina; Olefsky, Jerrold M.; Ginsberg, Mark H.
- Abstract
OBJECTIVE--Many prevalent diseases of advanced societies, such as obesity-induced type 2 diabetes, are linked to indolent mononuclear cell-dependent inflammation. We previously proposed that blockade of α4 integrin signaling can inhibit inflammation while limiting mechanism-based toxicities of loss of α4 function. Thus, we hypothesized that mice bearing an α4(Y991A) mutation, which blocks signaling, would be protected from development of high-fat diet-induced insulin resistance. RESEARCH DESIGN AND METHODS--Six- to eight-week-old wild-type and α4(Y991A) C57B1/6 male mice were placed on either a high-fat diet that derived 60% calories from lipids or a chow diet. Metabolic testing was performed after 16-22 weeks of diet. RESULTS--α4(Y991A) mice were protected from development of high-fat diet--induced insulin resistance. This protection was conferred on wild-type mice by α4(Y991A) bone marrow transplantation. In the reverse experiment, wild-type bone marrow renders high-fat diet-fed α4(Y991A) acceptor animals insulin resistant. Furthermore, fat-fed α4(Y991A) mice showed a dramatic reduction of monocyte/macrophages in adipose tissue. This reduction was due to reduced monocyte/macrophage migration rather than reduced monocyte chemoattractant protein-1 production. CONCLUSIONS--α4 integrins contribute to the development of HFD-induced insulin, resistance by mediating the trafficking of monocytes into adipose tissue; hence, blockade of α4 integrin signaling can prevent the development of obesity-induced insulin resistance. Diabetes 57:1842-1851, 2008
- Subjects
INTEGRINS; METABOLISM; FAT; OBESITY; DIET
- Publication
Diabetes, 2008, Vol 57, Issue 7, p1842
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db07-1751