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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

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

Address correspondence and reprint requests to Takeshi Nikawa, MD, PhD, Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: nikawa{at}nutr.med.tokushima-u.ac.jp

Abbreviations: 2-DG, 2-deoxyglucose; ELISA, enzyme-linked immunosorbent assay; H&E, hematoxylin and eosin; IL, interleukin; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; IRS, insulin receptor substrate; MCP, monocyte chemoattractant protein; SREBP-1c, sterol regulatory element binding protein-1c; SV, stromal vascular; TNF, tumor necrosis factor; WAT, white adipose tissue

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 AND METHODS—C57BL/6 (Cbl-b^+/+) or Cbl-b-deficient (Cbl-b^–/–) mice were subjected to insulin and glucose tolerance tests and a 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 a glucose challenge were always higher in elderly Cbl-b^–/– mice than age-matched Cbl-b^+/+ mice. Deficiency of the Cbl-b gene significantly decreased the uptake of 2-deoxyglucose into WAT and glucose infusion rate, whereas 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 (MCP)-1. Co-culture of Cbl-b^–/– macrophages with 3T3-L1 adipocytes induced leptin expression and dephosphorylation of insulin receptor substrate 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 macrophage activation by Cbl-b deficiency contributes to the peripheral insulin resistance and glucose intolerance via cytokines secreted from macrophages.

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