Dollet Lucile, Levrel Clara, Coskun Tamer, Le Lay Soazig, Le May Cedric, Ayer Audrey, Venara Quentin, Adams Andrew C, Gimeno Ruth E, Magré Jocelyne, Cariou Bertrand, Prieur Xavier
INSERM UMR S1087/CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France.
Lilly Research Laboratories, Indianapolis, IN.
Diabetes. 2016 Nov;65(11):3410-3417. doi: 10.2337/db16-0327. Epub 2016 Aug 23.
Fibroblast growth factor 21 (FGF21) was shown to improve metabolic homeostasis, at least partly by controlling white adipocyte profile and adiponectin secretion. Here, we studied its effect on adipocyte dysfunction in the context of Berardinelli-Seip congenital lipodystrophy (BSCL) linked to seipin deficiency. Bscl2 mice displayed a progressive adipose tissue loss with aging as evidenced by the altered profile of residual fat pads and the decrease in adiponectin plasma levels in 12- vs. 4-week-old animals. Aiming to prevent this impairment, we treated 6-week-old Bscl2 mice with an FGF21 analog (LY2405319) for a period of 28 days. FGF21 treatment increased adiponectin plasma levels and normalized insulin sensitivity in Bscl2 mice by improving the white adipose tissue gene expression pattern. To further decipher the molecular pathways altered by seipin deficiency in mature adipocytes, we developed a unique inducible seipin knockdown cell line (SKD). SKD showed chronic activation of the p38 MAPK pathway associated with apoptotic cell death. Interestingly, FGF21 treatment exerted an antistress effect on SKD cells, reducing p38 MAPK phosphorylation and limiting mature adipocyte loss. Our data demonstrate that FGF21 treatment improves the metabolic profile of Bscl2 lipodystrophic mice, partly by improving mature adipocyte maintenance through suppression of cellular stress via inhibition of p38 MAPK activity.
成纤维细胞生长因子21（FGF21）已被证明可改善代谢稳态，至少部分是通过控制白色脂肪细胞特征和脂联素分泌来实现的。在此，我们研究了其在与seipin缺乏相关的贝拉尔迪内利 - 塞普先天性脂肪营养不良（BSCL）背景下对脂肪细胞功能障碍的影响。Bscl2小鼠随着年龄增长出现渐进性脂肪组织丢失，12周龄与4周龄动物相比，残余脂肪垫特征改变以及血浆脂联素水平降低证明了这一点。为了预防这种损害，我们用FGF21类似物（LY2405319）对6周龄的Bscl2小鼠进行了为期28天的治疗。FGF21治疗提高了Bscl2小鼠的血浆脂联素水平，并通过改善白色脂肪组织基因表达模式使胰岛素敏感性恢复正常。为了进一步解读成熟脂肪细胞中seipin缺乏所改变的分子途径，我们构建了一种独特的可诱导seipin敲低细胞系（SKD）。SKD显示出与凋亡性细胞死亡相关的p38 MAPK途径的慢性激活。有趣的是，FGF21治疗对SKD细胞发挥了抗应激作用，减少了p38 MAPK磷酸化并限制了成熟脂肪细胞的丢失。我们的数据表明，FGF21治疗改善了Bscl2脂肪营养不良小鼠的代谢状况，部分是通过抑制p38 MAPK活性来抑制细胞应激，从而改善成熟脂肪细胞的维持。
