Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1α pathway
Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1α pathway
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DOI：
10.1073/pnas.1006962107
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发表时间：
2010-07-13
影响因子：
11.1
通讯作者：
Gromada, Jesper
中科院分区：
文献类型：
--
作者：
Chau, Mary D. L.;Gao, Jiaping;Gromada, Jesper
成纤维细胞生长因子21（FGF 21）已被鉴定为有效的代谢调节剂。对患有饮食诱导或遗传性肥胖和糖尿病的啮齿动物和恒河猴给予重组FGF 21蛋白，可发挥强的抗高血糖和降低血糖的作用，并减轻体重。尽管FGF 21在葡萄糖、脂质和能量稳态调节中的重要性，但FGF 21作为代谢调节剂发挥作用的机制在很大程度上仍不清楚。在这里，我们证明了FGF 21通过激活AMP活化蛋白激酶（AMPK）和sirtuin 1（SIRT 1）调节脂肪细胞的能量稳态，从而增强线粒体氧化功能。通过FGF 21处理，ob/ob小鼠脂肪细胞以及白色脂肪组织中AMPK磷酸化水平增加。FGF 21处理增加了细胞NAD（+）水平，导致SIRT 1的激活及其下游靶点过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1 α）和组蛋白3的脱乙酰化。脂肪细胞中FGF 21对AMPK和SIRT 1的激活增强了线粒体的氧化能力，这一点可以通过增加耗氧量、柠檬酸合酶活性和诱导关键代谢基因来证明。FGF 21对线粒体功能的影响需要丝氨酸/苏氨酸激酶11（STK 11/LKB 1），其激活AMPK。AMPK、SIRT 1和PGC-1 α活性的抑制减弱了FGF 21对氧消耗和基因表达的影响，表明FGF 21通过AMPK-SIRT 1-PGC 1 α依赖性机制调节脂肪细胞中的线粒体活性并增强氧化能力。
Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes exerts strong antihyperglycemic and triglyceride-lowering effects and reduction of body weight. Despite the importance of FGF21 in the regulation of glucose, lipid, and energy homeostasis, the mechanisms by which FGF21 functions as a metabolic regulator remain largely unknown. Here we demonstrate that FGF21 regulates energy homeostasis in adipocytes through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), resulting in enhanced mitochondrial oxidative function. AMPK phosphorylation levels were increased by FGF21 treatment in adipocytes as well as in white adipose tissue from ob/ob mice. FGF21 treatment increased cellular NAD(+) levels, leading to activation of SIRT1 and deacetylation of its downstream targets, peroxisome proliferator-activated receptor-gamma coactivator- 1 alpha (PGC-1 alpha) and histone 3. Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1 alpha activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an AMPK-SIRT1-PGC1 alpha-dependent mechanism in adipocytes.