title: Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice.
abstract: 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.
  
  
  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-alpha, 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.
authors.affiliation: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirasaka
authors.forename: Shohei
authors.initials: S
authors.lastname: Kohno
authors.forename: Jumpei
authors.initials: J
authors.lastname: Goto
authors.forename: Harumi
authors.initials: H
authors.lastname: Furochi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Mawatari
authors.forename: Nagakatsu
authors.initials: N
authors.lastname: Harada
authors.forename: Toshio
authors.initials: T
authors.lastname: Hosaka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakaya
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ishidoh
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Obata
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Ebina
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Kishi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nikawa
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D003433:Crosses, Genetic; D004734:Energy Metabolism; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008262:Macrophage Activation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency* / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C118387:Cblb protein, mouse; D007328:Insulin; D050721:Proto-Oncogene Proteins c-cbl; D005947:Glucose