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Diabetes Publish Ahead of Print published online ahead of print April 21, 2008
DOI: 10.2337/db07-1751
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Original Research

Blockade of {alpha}4 integrin Signaling Ameliorates the Metabolic Consequences of High Fat Diet-Induced Obesity

Chloé C. Féral, PhD1,,2, Jaap G. Neels, PhD1, Christiane Kummer, PhD1, Marina Slepak, BS1, Jerrold M. Olefsky, MD PhD1, and Mark H. Ginsberg, MD1

1Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0726
2INSERM, U634, Nice F-06107, France, Nice-Sophia Antipolis University. 28 avenue de Valombrose, Nice cedex 2

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 (HFD)-induced insulin resistance.

Research Design and Methods: 6-8 weeks old wild-type (WT) and {alpha}4(Y991A) C57Bl/6 male mice were placed on either a HFD that derived 60% calories from lipids, or a chow diet. Metabolic testing was performed after 16 to 22 weeks of diet.

Results: {alpha}4(Y991A) mice were protected from development of HFD-induced insulin resistance. This protection was conferred on WT mice by {alpha}4(Y991A) bone marrow transplantation. In the reverse experiment, WT bone marrow renders HFD-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 (MCP-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.

Correspondence: cferal{at}unice.fr


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