Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice
Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice
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DOI：
10.1152/ajpendo.00418.2014
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发表时间：
2015-03-01
影响因子：
5.1
通讯作者：
Shimotoyodome, Akira
中科院分区：
文献类型：
--
作者：
Chen, Shu;Okahara, Fumiaki;Shimotoyodome, Akira
葡萄糖依赖性促胰岛素多肽（GIP）是一种响应膳食脂肪和葡萄糖而分泌的肠道激素。肥胖和糖尿病患者的血液GIP水平升高。GIP刺激促炎基因表达并损害培养的脂肪细胞的胰岛素敏感性。在肥胖症中，脂肪组织内的缺氧可诱导炎症。本研究的目的是1）检查体内脂肪组织中增加的GIP信号传导的促炎作用和2）澄清脂肪组织炎症中GIP和缺氧信号传导之间的关联。我们给misty（瘦）和db/db（肥胖）小鼠腹腔注射GIP，并检查脂肪组织炎症和胰岛素敏感性。我们还研究了GIP和缺氧对3T3-L1脂肪细胞中GIP受体（GIPR）基因和促炎基因表达的影响。GIP给药增加了db/db小鼠单核细胞趋化蛋白-1（MCP-1）表达和巨噬细胞向脂肪组织的浸润，并增加了血糖。小鼠脂肪组织中GIPR和HIF-1 α表达呈正相关。GIPR表达在分化的脂肪细胞中显着增加。GIP处理的脂肪细胞增加MCP-1和白细胞介素-6（IL-6）的生产。与RAW 264巨噬细胞或在缺氧条件下培养的脂肪细胞表达更多的GIPR和HIF-1 α，GIP处理增加纤溶酶原激活物抑制剂1和IL-6的基因表达。HIF-1 α基因沉默降低巨噬细胞和低氧诱导的GIPR表达和GIP诱导的IL-6表达。因此，增加的GIP信号传导在肥胖小鼠的脂肪组织炎症中起重要作用，从而导致胰岛素抵抗，HIF-1 α可能有助于这一过程。
Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1 alpha, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1 alpha gene silencing diminished both macrophage-and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1 alpha may contribute to this process.