FGF21 Improves the Adipocyte Dysfunction Related to Seipin Deficiency
FGF21 Improves the Adipocyte Dysfunction Related to Seipin Deficiency
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DOI：
10.2337/db16-0327
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发表时间：
2016-11-01
期刊：
影响因子：
7.7
通讯作者：
Prieur, Xavier
中科院分区：
文献类型：
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作者：
Dollet, Lucile;Levrel, Clara;Prieur, Xavier
成纤维细胞生长因子21（FGF 21）被证明可以改善代谢稳态，至少部分是通过控制白色脂肪细胞分布和脂联素分泌。在这里，我们研究了它对脂肪细胞功能障碍的贝拉尔迪内利-赛普先天性脂肪营养不良（BSCL）的背景下，与seipin缺乏症。Bscl 2（-/-）小鼠显示出随着年龄增长的进行性脂肪组织损失，如12周龄与4周龄动物中残余脂肪垫的改变和脂联素血浆水平的降低所证明的。为了防止这种损伤，我们用FGF 21类似物（LY 2405319）处理6周龄的Bscl 2（-/-）小鼠28天。FGF 21治疗通过改善白色脂肪组织基因表达模式增加了Bscl 2（-/-）小鼠的脂联素血浆水平并使胰岛素敏感性正常化。为了进一步解释成熟脂肪细胞中seipin缺乏所改变的分子途径，我们开发了一种独特的可诱导seipin敲低细胞系（SKD）。SKD显示与凋亡性细胞死亡相关的p38 MAPK通路的慢性激活。有趣的是，FGF 21处理对SKD细胞产生了抗应激作用，减少了p38 MAPK磷酸化并限制了成熟脂肪细胞的损失。我们的数据表明，FGF 21治疗改善了Bscl 2（-/-）脂肪营养不良小鼠的代谢特征，部分原因是通过抑制p38 MAPK活性抑制细胞应激来改善成熟脂肪细胞的维持。
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.