Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance
Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance
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DOI：
10.2337/db12-0976
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发表时间：
2013-06-01
期刊：
影响因子：
7.7
通讯作者：
Lyssenko, Valeriya
中科院分区：
文献类型：
--
作者：
Ahlqvist, Emma;Osmark, Peter;Lyssenko, Valeriya
肥胖症的低度炎症与巨噬细胞源性细胞因子骨桥蛋白（OPN）在脂肪组织中的积累以及局部和全身胰岛素抵抗的诱导有关。由于葡萄糖依赖性促胰岛素多肽（GIP）是脂肪生成的强刺激物，并且可能在肥胖的发展中起作用，因此我们探索GIP是否直接刺激脂肪组织中的OPN表达，从而诱导胰岛素抵抗。GIP以剂量依赖性方式刺激大鼠原代脂肪细胞OPN蛋白表达。肥胖者脂肪组织中OPN mRNA水平较高（0.13 ± 0.04 vs.0.04 ± 0.01，P < 0.05），与胰岛素敏感性呈负相关（r =-0.24，P = 0.001）。GIP受体（GIPR）（rs 10423928）基因的一个常见变异体与跨膜活性所需的较低数量的外显子9含亚型相关。受体功能降低的A等位基因携带者表现出较低的脂肪组织OPN mRNA水平和较好的胰岛素敏感性。总之，这些数据表明GIP不仅作为肠促胰岛素激素，而且作为脂肪组织中炎症和胰岛素抵抗的触发因素。GIPR rs 10423928 A等位基因的携带者通过降低GIP效应显示出保护性质。确定脂肪组织中GIP和OPN之间的这种前所未有的联系可能为治疗干预开辟新途径。
Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 +/- 0.04 vs. 0.04 +/- 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.