Blockade Of Alpha 4 Integrin Signaling Ameliorates The Metabolic Consequences Of High-Fat Diet-Induced Obesity

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 alpha 4 integrin signaling can inhibit inflammation while limiting mechanism-based toxicities of loss of (alpha 4 function. Thus, we hypothesized that mice bearing an alpha 4(Y991A) mutation, which blocks signaling, would be protected from development of high-fat diet-induced insulin resistance.RESEARCH DESIGN AND METHODS-Six- to eight-weekold wild-type and alpha 4(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-alpha 4(Y991A) mice were protected from development of high-fat diet-induced insulin resistance. This protection was conferred on wild-type mice by alpha 4(Y991A) bone marrow transplantation. In the reverse experiment, wild-type bone marrow renders high-fat diet-fed alpha 4(Y991A) acceptor animals insulin resistant. Furthermore, fat-fed alpha 4(Y991A) mice showed dramatic reduction of morrocyte/macrophages in adipose tissue. This reduction was due to reduced morrocyte/macrophage migration rather than reduced monocyte chemoattractant protein-1 production.CONCLUSIONS-alpha 4 integrins contribute to the development of HFD-induced insulin resistance by mediating the trafficking of monocytes into adipose tissue; hence, blockade of alpha 4 integrin signaling can prevent the development of obesity-induced insulin resistance.