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Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice

¹Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503
²Department of Nutrition and Metabolism, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503;
³The Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514;
⁴Division of Molecular Genetics, The Institute for Enzyme Research, The University of Tokushima, Tokushima 770-8503;
⁵Department of Microbiology, Columbia University, New York, NY, USA;
⁶National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.

Correspondence: nikawa{at}nutr.med.tokushima-u.ac.jp

Objective:c-Cbl plays an important role in whole-body fuel homeostasis by regulating insulin action. In the present study, we examined the role of Cbl-b, another member of the Cbl family, in insulin action.

Research Design:C57BL/6 (Cbl-b^+/+) or Cbl-b-deficient (Cbl-b^-/-) mice were subjected to insulin and glucose tolerance tests and hyperinsulinemic-euglycemic clamp test. Infiltration of macrophages into white adipose tissue (WAT) was assessed by immunohistochemistry and flow cytometry. We examined macrophage activation using co-cultures of 3T3-L1 adipocytes and peritoneal macrophages.

Results:Elderly Cbl-b^-/- mice developed glucose intolerance and peripheral insulin resistance; serum insulin concentrations after glucose challenge were always higher in elderly Cbl-b^-/- mice than age-matched Cbl-b^+/+ mice. Deficiency of Cbl-b gene significantly decreased the uptake of 2-deoxyglucose into WAT and glucose infusion rate, while fatty liver was apparent in elderly Cbl-b^-/- mice. Cbl-b deficiency was associated with infiltration of macrophages into the WAT and expression of cytokines, such as tumor necrosis factor-, interleukin-6 and monocyte chemoattractant protein-1 (MCP-1). Co-culture of Cbl-b^-/- macrophages with 3T3-L1 adipocytes induced leptin expression and dephospholylation of IRS-1, leading to impaired glucose uptake in adipocytes. Furthermore, Vav1, a key factor in macrophage activation, was highly phosphorylated in peritoneal Cbl-b^-/- macrophages, compared with Cbl-b^+/+ macrophages. Treatment with a neutralizing anti-MCP-1 antibody improved peripheral insulin resistance and macrophage infiltration into WAT in elderly Cbl-b^-/- mice.

Conclusions:Cbl-b is a negative regulator of macrophage infiltration and activation, and that macrophage activation by Cbl-b deficiency contributes to the peripheral insulin resistance and glucose intolerance via cytokines secreted from macrophages.

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