Nat Commun. 2018 Feb 12;9(1):636. doi: 10.1038/s41467-018-03038-w.

Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood.

Yuan X^1,², Tsujimoto K¹, Hashimoto K³, Kawahori K¹, Hanzawa N¹, Hamaguchi M^1,², Seki T¹, Nawa M⁴, Ehara T^1,⁵, Kitamura Y⁵, Hatada I⁶, Konishi M⁷, Itoh N⁸, Nakagawa Y^9,¹⁰, Shimano H^9,¹⁰, Takai-Igarashi T¹¹, Kamei Y¹², Ogawa Y^13,^14,^15,¹⁶.

Author information

1: Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
2: Department of Molecular and Cellular Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
3: Department of Preemptive Medicine and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. khashimoto.mem@tmd.ac.jp.
4: Laboratory of Cytometry and Proteome Research, Nanken-Kyoten and Research Core Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
5: Wellness and Nutrition Science Institute, Morinaga Milk Industry Co., Ltd, 5-1-83, Higashihara, Zama, Kanagawa, 252-8583, Japan.
6: Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512, Japan.
7: Department of Microbial Chemistry, Kobe Pharmaceutical University, 1-19-4, Motoyama-kitamachi, Higashinada-ku, Kobe, Hyogo, 658-8558, Japan.
8: Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
9: Department of Internal Medicine (Metabolism and Endocrinology), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
10: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
11: Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8573, Japan.
12: Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, 1-5 Hangi-cho, Shimogamo, Sakyo-ku, Kyoto, 606-8522, Japan.
13: Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. yogawa@intmed3.med.kyushu-u.ac.jp.
14: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. yogawa@intmed3.med.kyushu-u.ac.jp.
15: Japan Agency for Medical Research and Development, CREST, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan. yogawa@intmed3.med.kyushu-u.ac.jp.
16: Department of Molecular and Cellular Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. yogawa@intmed3.med.kyushu-u.ac.jp.

Abstract

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.