Ye Min, Lu Weiqin, Wang Xiaojie, Wang Cong, Abbruzzese James L, Liang Guang, Li Xiaokun, Luo Yongde
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Endocrinology. 2016 Dec;157(12):4754-4769. doi: 10.1210/en.2016-1710. Epub 2016 Oct 3.
The antiobese and antidiabetic fibroblast growth factor 21 (FGF21) regulates lipid metabolism and energy homeostasis by targeting the βKlotho-FGFR1 (fibroblast growth factor receptor 1) binary complex in adipose tissue adipocytes. Because lipid droplet is the organelle responsible for storing lipid energy in adipocytes, it is the plausible target of FGF21 action. However, the impact of the FGF21-βKlotho-FGFR1 signaling pathway on the functions of the lipid droplet is not clearly understood. Using our mouse models of adipocyte-specific FGFR1 ablation and hepatic overexpression of FGF21 with diet-induced obesity established previously, we analyzed the alterations of the pathways involved in energy and substrate metabolism that is attributable to the dynamic functions of the lipid droplet. In addition to the previous reports showing that FGFR1 deficiency abrogated lipolysis, fatty acid oxidation, and energy expenditure promoted by the elevated FGF21 signal, we observed that the deficiency up-regulated the biosynthesis and remodeling of membrane phospholipids that are important for the biogenesis and expansion of the droplet, whereas the enhanced FGF21 signal constrained the biosynthesis of phospholipids. As a result, the loss of adipose FGFR1 led to a sustained droplet expansion and endoplasmic reticulum (ER) stress, whereas the enhanced FGF21 signal suppressed them in obesogenesis. These new findings reveal that the FGF21-βKlotho-FGFR1 signaling axis plays roles in maintaining phospholipid homeostasis and the dynamic functions of the lipid droplet, whereas protecting against ER stress, and suggest a potential link of phospholipid biosynthesis, lipid droplet dynamics, ER stress, and energy homeostasis in adipose tissue coordinated by this signaling axis.
抗肥胖和抗糖尿病的成纤维细胞生长因子21（FGF21）通过作用于脂肪组织脂肪细胞中的βKlotho-FGFR1（成纤维细胞生长因子受体1）二元复合物来调节脂质代谢和能量稳态。由于脂滴是负责在脂肪细胞中储存脂质能量的细胞器，因此它是FGF21作用的合理靶点。然而，FGF21-βKlotho-FGFR1信号通路对脂滴功能的影响尚不清楚。利用我们先前建立的脂肪细胞特异性FGFR1缺失和饮食诱导肥胖时FGF21肝脏过表达的小鼠模型，我们分析了归因于脂滴动态功能的能量和底物代谢相关途径的改变。除了先前的报道表明FGFR1缺乏消除了FGF21信号升高所促进的脂解、脂肪酸氧化和能量消耗外，我们还观察到该缺乏上调了对脂滴生物发生和扩张很重要的膜磷脂的生物合成和重塑，而增强的FGF21信号则抑制了磷脂的生物合成。结果，脂肪组织中FGFR1的缺失导致脂滴持续扩张和内质网（ER）应激，而增强的FGF21信号在肥胖发生过程中抑制了它们。这些新发现揭示了FGF21-βKlotho-FGFR1信号轴在维持磷脂稳态和脂滴动态功能中发挥作用，同时预防ER应激，并表明该信号轴协调了脂肪组织中磷脂生物合成、脂滴动态、ER应激和能量稳态之间的潜在联系。
