Blockade of α4 Integrin Signaling Ameliorates the Metabolic Consequences of High-Fat Diet–Induced Obesity

  1. Chloé C. Féral12,
  2. Jaap G. Neels1,
  3. Christiane Kummer1,
  4. Marina Slepak1,
  5. Jerrold M. Olefsky1 and
  6. Mark H. Ginsberg1
  1. 1Department of Medicine, University of California, San Diego, La Jolla, California
  2. 2Institut National de la Santé et de la Recherche Médicale, U634, Nice-Sophia Antipolis University, Nice, France
  1. Corresponding author: Chloé C. Féral, cferal{at}


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) 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—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.


  • Published ahead of print at on 21 April 2008.

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    • Accepted April 14, 2008.
    • Received December 13, 2007.
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  1. Diabetes vol. 57 no. 7 1842-1851
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