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ICAM-1 and β2 Integrin Deficiency Impairs Fat Oxidation and Insulin Metabolism during Fasting

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Abstract

Intercellular adhesion molecule 1 (ICAM-1) and β2 integrins play critical roles in immune responses. ICAM-1 may also participate in regulation of energy balance because ICAM-1-deficient mice become obese on a high-fat diet. We show that mice deficient in these adhesion receptors are unable to respond to fasting by up-regulation of fatty acid oxidation. Normal mice, when fasted, exhibit reduced circulating neutrophil counts and increased ICAM-1 expression and neutrophil recruitment in liver. Mice lacking ICAM-1 or β2 integrins fail to show these responses—instead they become hypoglycemic with steatotic livers. Fasting ICAM-1-deficient mice reduce insulin more slowly than wild-type mice. This produces fasting hyperinsulinemia that prevents activation of adenosine mono-phosphate (AMP)-activated protein kinase in muscles and liver, which results in decreased import of long chain fatty acids into mitochondria. Thus, we show a new role for immune cells and their adhesion receptors in regulating metabolic response to fasting.

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Acknowledgments

We thank Barbara Corkey, Jeffrey Friedman, Ronald Kahn, and Harvey Lodish for helpful discussions and the many scientists who patiently listened to our story and gave us advice. We thank Leonardo Ganem for PPAR analysis. The work was supported by National Heart, Lung, and Blood Institute/NIH grant RO1-HL53756 to DDW.TWF was supported by a research stipend from the Deutsche Forschungsgemeinschaft (FE 537/1-1).

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Authors and Affiliations

  1. The CBR Institute for Biomedical Research, 800 Huntington Avenue, Boston, Massachusetts, 02115, USA

    Aleksandar M Babic, Hong-Wei Wang, Margaret J Lai, Thomas W Felbinger, Peter C Burger & Denisa D Wagner

  2. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Aleksandar M Babic, Hong-Wei Wang, Peter C Burger & Denisa D Wagner

  3. Division of Clinical Pathology/Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

    Aleksandar M Babic

  4. Metabolic Diseases Physiology and Pharmacology, Millennium Pharmaceuticals, Cambridge, Massuchusetts, USA

    Thomas G Daniels & Alain Stricker-Krongrad

  5. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA

    Thomas W Felbinger

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  1. Aleksandar M Babic
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  2. Hong-Wei Wang
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  8. Denisa D Wagner
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Correspondence to Denisa D Wagner.

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Note: Thomas Daniels and Alain Stricker-Krongrad were employees of Millennium Pharmaceuticals.

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Babic, A.M., Wang, HW., Lai, M.J. et al. ICAM-1 and β2 Integrin Deficiency Impairs Fat Oxidation and Insulin Metabolism during Fasting. Mol Med 10, 72–79 (2004). https://doi.org/10.2119/2004-00038.Wagner

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  • DOI: https://doi.org/10.2119/2004-00038.Wagner

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