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Published online April 21, 2008
Diabetes 57:1842-1851, 2008
DOI: 10.2337/db07-1751
© 2008 by the American Diabetes Association
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Blockade of {alpha}4 Integrin Signaling Ameliorates the Metabolic Consequences of High-Fat Diet–Induced Obesity

Chloé C. Féral1,2, Jaap G. Neels1, Christiane Kummer1, Marina Slepak1, Jerrold M. Olefsky1, and Mark H. Ginsberg1

1 Department of Medicine, University of California, San Diego, La Jolla, California
2 Institut National de la Santé et de la Recherche Médicale, U634, Nice-Sophia Antipolis University, Nice, France

Corresponding author: Chloé C. Féral, cferal{at}unice.fr

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-week-old wild-type and {alpha}4(Y991A) C57Bl/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 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—{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.


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