Author: 〇黄 菲1、高 靖1、自見 英治郎1,2
Affiliation: 1九大 院歯 口腔細胞工学、2九大 院歯 OBTセンター
Abstract:
Postmenopausal women have been reported to be at increased risk of fractures due to decreased bone density, diabetes and cardiovascular disorders due to weight gain. We and others have previously reported that anti-RANKL antibodies and NIK inhibitors that suppress the differentiation of osteoclasts not only suppress bone loss after ovariectomy, but also suppress weight gain, suggesting that common regulatory mechanism exists between bone loss and gain weight caused by estrogen deficiency. The purpose of this study is to investigate the mechanism that causes the decrease in bone density and weight gain due to estrogen deficiency at the cellular and molecular levels. We generated knock-in mice that NF-κB activity was enhanced, by expressing a mutant p65 with an alanine-to-serine substitution at position 534 (the murine homolog of human Ser536) (S534AKI mice). Wild-type (WT) and S534AKI mice were performed sham operation or ovariectomy (OVX) and further maintained by normal diet for 10 weeks to analyze the energy and bone metabolism. Body weight changes were measured weekly, and at 10 weeks, white and brown adipose tissue weight was measured, and adipose and liver tissue sections were prepared. Insulin tolerance test (ITT) were performed at 8 weeks. Three-dimensional bone reconstruction and bone mineral density (BMD) were measured at 4 weeks by Micro-computed tomography (µCT). S534AKI mice gained more weight than WT mice in OVX group. Correspondingly, the size and weight of both white and brown adipose tissue was bigger in S534AKI mice compared with WT mice in OVX group. Histological analysis showed the size of adipocyte of S534AKI mice was also larger than WT mice. S534AKI mice in OVX group had a less hepatic glycogen storage than other groups. S534AKI mice in OVX group were resistant to the glucose-lowering effect of insulin compared with WT mice. In addition, the BMD of both WT mice and S534AKI mice decreased 4 weeks after OVX. However, S534AKI mice showed lower BMD than WT mice in both sham and OVX group. Taken together, NF-κB activity might be involved in bone loss and weight gain as a common regulator due to estrogen deficiency.
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