CXCL12-CXCR4 pathway activates brown adipocytes and induces insulin resistance in CXCR4-deficient mice under high-fat diet
CXCL12-CXCR4 pathway activates brown adipocytes and induces insulin resistance in CXCR4-deficient mice under high-fat diet
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DOI：
10.1038/s41598-019-42127-8
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发表时间：
2019-04-16
影响因子：
4.6
通讯作者：
Yokote, Koutaro
中科院分区：
文献类型：
--
作者：
Kurita, Kenichi;Ishikawa, Ko;Yokote, Koutaro
棕色脂肪组织（BAT）在能量消耗中起作用，并参与营养代谢。C-X-C趋化因子配体12（CXCL 12）-CXCR 4通路调节免疫、神经和心血管系统并影响脂肪组织。在这里，我们研究了这个途径作为BAT激活剂的作用。解偶联蛋白1 mRNA和蛋白质水平和耗氧量增加的棕色脂肪细胞用100 nM CXCL 12肽处理。CXCL 12介导的P38和细胞外信号调节激酶（ERK）水平的上调被每种抑制剂降低。因此，CXCL 12-CXCR 4通路通过作用于该通路下游的P38和ERK激活棕色脂肪细胞。产生仅在棕色脂肪细胞中具有CXCR 4缺陷的小鼠，并用高脂饮食（HFD）喂养。这些小鼠在注射葡萄糖后体重和血糖增加。长期暴露于HFD使注射葡萄糖后的血糖水平恶化。在用HFD喂养的基因敲除小鼠中，胰岛素敏感性加剧。CXCL 12基因敲除小鼠的血脂指标和CXCL 12水平与对照小鼠相似。这些结果表明，CXCL 12-CXCR 4途径诱导棕色脂肪细胞活性，并影响HFD负荷下的营养代谢。
Brown adipose tissue (BAT) plays a role in energy expenditure and is involved in nutrient metabolism. C-X-C chemokine ligand 12 (CXCL12)-CXCR4 pathway regulates the immune, nervous, and cardiovascular systems and affects the adipose tissue. Here, we investigated the role of this pathway as an activator of BAT. Uncoupling protein 1 mRNA and protein levels and oxygen consumption increased in the brown adipocytes treated with 100 nM CXCL12 peptide. CXCL12-mediated upregulation in P38 and extracellular signal-regulated kinase (ERK) levels was reduced by each inhibitor. Thus, the CXCL12-CXCR4 pathway activated the brown adipocytes through P38 and ERK that acted downstream of this pathway. Mice with CXCR4 defects only in the brown adipocytes were generated and fed with high-fat diet (HFD). Body weight and blood glucose after glucose injection increased in these mice. Long-term exposure to HFD deteriorated blood glucose level after glucose injection. Insulin sensitivity was exacerbated in the knockout mice fed with HFD. Serum lipid parameters and CXCL12 level in knockout mice were similar to those in control mice. These results suggest that the CXCL12-CXCR4 pathway induces brown adipocyte activity and affects nutrient metabolism under HFD load.