Abstract
Intercellular adhesion molecule 1 (ICAM-1) and beta2 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 beta2 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.
Highlights
Leukocyte adhesion molecules play an essential role in inflammation and immunosurveillance
CD18-deficient mice were kept on antibiotics (Baytril) until 7 d prior to respiratory quotient (RQ) measurement because they succumb to infection
We have seen excessive weight gain in mice lacking CD11b [7] and, more recently, in mice overexpressing soluble Intercellular adhesion molecule1 (ICAM-1), which acts as an inhibitor of leukocyte recruitment (Hong-Wei Wang, manuscript submitted for publication)
Summary
Leukocyte adhesion molecules play an essential role in inflammation and immunosurveillance. Intercellular adhesion molecule (ICAM-1) is a member of the immunoglobulin super family of adhesion molecules [1] that is expressed on many cell types including endothelium, hepatocytes, and leukocytes. Two main ligands for ICAM-1 are CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), which are members of the leukocyte-specific β2 integrin (CD18) family that comprises at least 2 other members. Mice deficient in ICAM-1 have impaired immune function and decreased inflammatory response, reflected in impaired activation and migration of leukocytes to places of inflammation, reduced contact hypersensitivity and impaired ability of spleen cells to act as stimulators in mixed lymphocyte responses [4]. Mice deficient in CD18 expression showed impaired activation and migration of leukocytes to places of inflammation and impaired T cell proliferation in response to T-cell receptor activation that was more extensive than in ICAM-1–deficient mice [5]. CD18 deficiency causes a severe immunodeficiency condition called Leukocyte Adhesion Deficiency Syndrome type I (LAD I) [6]
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