Yuan Xunmei, Tsujimoto Kazutaka, Hashimoto Koshi, Kawahori Kenichi, Hanzawa Nozomi, Hamaguchi Miho, Seki Takami, Nawa Makiko, Ehara Tatsuya, Kitamura Yohei, Hatada Izuho, Konishi Morichika, Itoh Nobuyuki, Nakagawa Yoshimi, Shimano Hitoshi, Takai-Igarashi Takako, Kamei Yasutomi, Ogawa Yoshihiro
Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Department of Molecular and Cellular Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Nat Commun. 2018 Feb 12;9(1):636. doi: 10.1038/s41467-018-03038-w.
The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) α-dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction of hepatic FGF21 expression after PPARα activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity.
动物在生命早期所接触的营养环境可导致基因组发生表观遗传变化，从而影响其成年后患肥胖症的风险。在此，我们证明成纤维细胞生长因子21基因（Fgf21）在出生后肝脏中会发生过氧化物酶体增殖物激活受体（PPAR）α依赖性DNA去甲基化。在哺乳期通过PPARα的药物激活可增强Fgf21甲基化的降低。我们还发现，Fgf21的DNA甲基化状态一旦在生命早期确立，就相对稳定并持续至成年期。DNA甲基化降低与PPARα激活后肝脏FGF21表达的诱导增强相关，这可能部分解释了成年期饮食诱导肥胖的减轻。我们提出，Fgf21甲基化代表了一种持续至成年期的表观遗传记忆形式，并且它可能在肥胖的发育编程中发挥作用。
