Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice
Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice
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DOI：
10.2337/db06-1768
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发表时间：
2007-10-01
期刊：
影响因子：
7.7
通讯作者：
Nikawa, Takeshi
中科院分区：
文献类型：
--
作者：
Hirasaka, Katsuya;Kohno, Shohei;Nikawa, Takeshi
APPLICATIVE-c-Cbl通过调节胰岛素作用在全身燃料稳态中起重要作用。研究设计和方法-C57 BU 6（Cbl-b（+/+））或Cbl-b缺陷（Cbl-b（-/-））小鼠进行胰岛素和葡萄糖耐量试验和高胰岛素-正常血糖钳夹试验。通过免疫组织化学和流式细胞术评估巨噬细胞向白色脂肪组织（WAT）的浸润。我们使用3 T3-L1脂肪细胞和腹腔巨噬细胞的共培养物检测了巨噬细胞的活化。老年Cbl-b（-/-）小鼠出现了葡萄糖耐受不良和外周胰岛素抵抗;葡萄糖激发后老年Cbl-b（-/-）小鼠的血清胰岛素浓度总是高于年龄匹配的Cbl-b+/+小鼠。Cbl-b基因的缺陷显着降低了WAT对2-脱氧葡萄糖的吸收和葡萄糖输注速率，而老年Cbl-b（-/-）小鼠中脂肪肝明显。Cbl-b缺乏与巨噬细胞浸润到WAT和细胞因子的表达相关，如肿瘤坏死因子-α、白细胞介素-6和单核细胞趋化蛋白（MCP）-1。Cbl-b-/-巨噬细胞与3 T3-L1脂肪细胞的共培养诱导瘦素表达和胰岛素受体底物1的去磷酸化，导致脂肪细胞中葡萄糖摄取受损。此外，与Cbl-b（+/+）巨噬细胞相比，Vav 1（巨噬细胞活化的关键因子）在腹膜Cbl-b-/-巨噬细胞中高度磷酸化。用中和性抗MCP-1抗体治疗改善了老年Cbl-b（-/-）mice.CONCLUSIONS- Cbl-b是巨噬细胞浸润和激活的负调节因子，Cbl-b缺乏引起的巨噬细胞激活通过巨噬细胞分泌的细胞因子导致外周胰岛素抵抗和葡萄糖耐受不良。
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-C57BU6 (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 inummohistochemistry 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 antiMCP-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.