Activation of lipoprotein lipase by glucose-dependent insulinotropic polypeptide in adipocytes - A role for a protein kinase B, LKB1, and AMP-activated protein kinase cascade
Activation of lipoprotein lipase by glucose-dependent insulinotropic polypeptide in adipocytes - A role for a protein kinase B, LKB1, and AMP-activated protein kinase cascade
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DOI：
10.1074/jbc.m609088200
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发表时间：
2007-03-23
影响因子：
4.8
通讯作者：
McIntosh, Christopher H. S.
中科院分区：
文献类型：
--
作者：
Kim, Su-Jin;Nian, Cuilan;McIntosh, Christopher H. S.
葡萄糖依赖的促胰岛素多肽(GIP)主要是由于其葡萄糖依赖的促胰岛素作用和调节β细胞增殖和存活的能力而被研究的。GIP对脂肪代谢的影响知之甚少，本研究旨在确定其对脂蛋白脂肪酶(LPL)的刺激作用的机制。在分化的3T3-L1脂肪细胞中，在胰岛素存在的情况下，GIP通过增加蛋白激酶B(PKB)的磷酸化、减少磷酸化的LKB1和AMP激活的蛋白激酶(AMPK)来增加LPL活性和甘油三酯的积累。使用RNA干扰抑制AMPK和应用AMPK抑制剂化合物C支持这一结论。相反，另一种主要的胰升糖素激素，胰升糖素样肽-1，对LPL活性或PKB、LKB1或AMPK磷酸化没有显著影响。培养的人皮下脂肪细胞对GIP的反应相似，但敏感性更高。温哥华糖尿病肥胖大鼠体内循环GIP水平的慢性升高导致LPL活性增加和外膜脂肪组织中甘油三酯积累增加，并与体外观察到的对PKB、LKB1和AMPK磷酸化的调节类似。这似乎是第一次证明了GIP刺激的信号转导通路涉及增加脂肪细胞中的脂肪储存。
Glucose-dependent insulinotropic polypeptide (GIP) has been mainly studied because of its glucose-dependent insulinotropic action and its ability to regulate beta-cell proliferation and survival. Considerably less is known about the effects of GIP on fat metabolism, and the present study was directed at identifying the mechanisms underlying its stimulatory action on lipoprotein lipase (LPL). In differentiated 3T3-L1 adipocytes, GIP, in the presence of insulin, increased LPL activity and triglyceride accumulation through a pathway involving increased phosphorylation of protein kinase B (PKB) and reductions in phosphorylated LKB1 and AMP-activated protein kinase (AMPK). Knockdown of AMPK using RNA interference and application of the AMPK inhibitor, Compound C, supported this conclusion. In contrast, the other major incretin hormone, glucagon-like peptide-1, exhibited no significant effects on LPL activity or PKB, LKB1, or AMPK phosphorylation. Cultured subcutaneous human adipocytes showed similar responses to GIP but with greater sensitivity. Chronic elevation of circulating GIP levels in the Vancouver diabetic fatty Zucker rat in vivo resulted in increased LPL activity and elevated triglyceride accumulation in epidydimal fat tissue, combined with a modulation of PKB, LKB1, and AMPK phosphorylation similar to that observed in vitro. This appears to be the first demonstration of a GIP-stimulated signal transduction pathway involved in increasing fat storage in adipocytes.