The hepatokine FGF21 is crucial for peroxisome proliferator-activated receptor-α agonist-induced amelioration of metabolic disorders in obese mice
The hepatokine FGF21 is crucial for peroxisome proliferator-activated receptor-α agonist-induced amelioration of metabolic disorders in obese mice
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DOI：
10.1074/jbc.m116.767590
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发表时间：
2017-06-02
影响因子：
4.8
通讯作者：
Kawada, Teruo
中科院分区：
文献类型：
--
作者：
Goto, Tsuyoshi;Hirata, Mariko;Kawada, Teruo
肥胖导致白色脂肪组织（WAT）和其他胰岛素反应器官（如骨骼肌）中的过量脂肪积累，增加胰岛素抵抗的风险，这可导致肥胖相关的代谢紊乱。过氧化物酶体增殖物激活受体-α（PPAR-alpha）是脂肪酸氧化的主要调节剂，已知其激活剂可改善高脂血症。然而，潜在的分子机制PPARalpha激活剂介导的减少肥胖和改善代谢紊乱在很大程度上是未知的。本研究探讨了过氧化物酶体增殖物激活受体α激动剂（非诺贝特）对肥胖小鼠糖代谢功能障碍的影响。非诺贝特治疗可减少高脂饮食肥胖小鼠的肥胖，并减轻肥胖诱导的葡萄糖代谢功能障碍。然而，非诺贝特治疗没有改善脂肪营养不良A-Zip/F1小鼠的葡萄糖代谢，这表明脂肪组织对于非诺贝特介导的葡萄糖代谢改善是重要的，尽管不能完全排除骨骼肌作用。此外，我们研究了肝细胞因子成纤维细胞生长因子21（FGF 21），它调节脂肪组织中的能量代谢的作用。在WT小鼠的WAT中，非诺贝特增强了与棕色脂肪细胞功能相关的基因的表达，如Ucp 1，Pgc 1a和Cpt 1b，但FGF 21缺陷小鼠没有。在高脂饮食喂养的WT小鼠的WAT中，非诺贝特增加能量消耗并减轻肥胖、全身胰岛素抵抗和脂肪细胞功能障碍，但在FGF 21-defi中没有-非诺贝特通过改善WAT功能障碍介导的肥胖小鼠全身葡萄糖代谢的改善。
Obesity causes excess fat accumulation in white adipose tissues (WAT) and also in other insulin-responsive organs such as the skeletal muscle, increasing the risk for insulin resistance, which can lead to obesity-related metabolic disorders. Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a master regulator of fatty acid oxidation whose activator is known to improve hyperlipidemia. However, the molecular mechanisms underlying PPAR alpha activator-mediated reduction in adiposity and improvement of metabolic disorders are largely unknown. In this study we investigated the effects of PPAR alpha agonist (fenofibrate) on glucose metabolism dysfunction in obese mice. Fenofibrate treatment reduced adiposity and attenuated obesity-induced dysfunctions of glucose metabolism in obese mice fed a high-fat diet. However, fenofibrate treatment did not improve glucose metabolism in lipodystrophic A-Zip/F1 mice, suggesting that adipose tissue is important for the fenofibrate-mediated amelioration of glucose metabolism, although skeletal muscle actions could not be completely excluded. Moreover, we investigated the role of the hepatokine fibroblast growth factor 21 (FGF21), which regulates energy metabolism in adipose tissue. In WAT of WT mice, but not of FGF21-deficient mice, fenofibrate enhanced the expression of genes related to brown adipocyte functions, such as Ucp1, Pgc1a, and Cpt1b. Fenofibrate increased energy expenditure and attenuated obesity, whole body insulin resistance, and adipocyte dysfunctions in WAT in high-fat-diet-fed WT mice but not in FGF21-defi-the fenofibrate-mediated improvement of whole body glucose metabolism in obese mice via the amelioration of WAT dysfunctions.