ESPE Abstracts (2016) 86 P-P1-443

The Collapse of the BDNF/POMC System in the Hypothalamus is Responsible for the Extreme Obesity with Hyperphagia Observed in Female Heterozygous MeCP2 Null Mice

Shota Fukuharaa, Hisakazu Nakajimaa, Kazuki Kodoa, Ikuyo Itoha, Keiichi Shigeharaa, Masaharu Morotoa, Satoru Sugimotoa, Jun Moria, Kitaro Kosakaa,b, Masafumi Morimotoa & Hajime Hosoia


aMedical Science Kyoto Prefectural University of Medicine, Kyoto, Japan; bSaiseikai Kyoto Hospital, Kyoto, Japan


Objective and hypotheses: The aim was to elucidate the mechanism underlying the extreme obesity observed in female heterozygous MeCP2 null mice fed a high-fat diet.

Method: We examined the molecular biology and physiology of female heterozygous MeCP2 null mice (Mecp2tm1.1Bird/J, MeCP2+/− mice) fed a high-fat diet (HFD) for 12 weeks since 4 weeks of age using analytical tools. C57/BL6 mice were used as controls.

Results: MeCP2+/− mice fed with HFD (MeCP2+/− +HFD mice) showed extreme obesity with hyperphagia since 7 weeks of age. However, O2 consumption and locomotor activity was not different between the MeCP2+/−+HFD mice and the controls fed a HFD (HFD mice). The amount of subcutaneous and visceral white adipose tissue was higher in the MeCP2+/−+HFD mice than in the HFD mice. Further, UCP1 mRNA and PGC1a mRNA expression in the brown adipose tissues was not different between the two groups. Serum leptin was higher in the MeCP2+/−+HFD mice than in the HFD mice. A dietary preference test revealed that the MeCP2+/−+HFD mice greatly preferred HFD than the HFD mice. AgRP mRNA and Ghrelin mRNA expression in the hypothalamus was higher in the MeCP2+/−+HFD mice than in the HFD mice. POMC mRNA expression in the hypothalamus was lower in the MeCP2+/−+HFD mice than in the HFD mice. Interestingly, mRNA and protein levels of BDNF in the hypothalamus were upregulated in the HFD mice, but downregulated in the MeCP2+/−+HFD mice. In addition, the phosphorylation of JAK2/STAT3 and Foxo1/AMPK in the hypothalamus was similar between the two groups.

Conclusion: The collapse of the BDNF/POMC system in the hypothalamus could lead to extreme obesity with hyperphagia in the MeCP2+/−+HFD mice. Epigenetic pathogenesis rather than disturbances in cell signaling appears to be the mechanism underlying the hyperphagia with leptin resistance observed in the MeCP2+/−+HFD mice.