[P1-3-49] The regulation of NF-κB signaling by p65 serine 534 phosphorylation is involved in both postmenopausal osteoporosis and weight gain
Keywords:NF-κB signaling、postmenopausal osteoporosis、obesity
Postmenopausal women are experienced bone loss and weight gain resulting in increased risk of fractures and developing varieties of diseases, including metabolic syndrome and breast cancer. In this study, we focused on NF-κB signaling and aimed to find out a common regulatory mechanism which might be involved in both postmenopausal osteoporosis and weight gain.
We generated knock-in mice in which the activity of NF-κB signaling is enhanced, by expressing a mutant p65 with a serine-to-alanine substitution at position 534 (S534A KI mice). Wild-type (WT) and S534A KI mice were performed sham operation or ovariectomy (OVX) to mimic the estrogen deficiency condition and further maintained by normal diet for 12 weeks to analyze the systemic energy metabolism and bone metabolism.
We found that even though WT and S534A KI mice have similar daily food intake, S534A KI 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 S534A KI mice compared with WT mice in OVX group. Histological analysis showed adipocyte size of S534A KI mice was also larger than WT mice in both sham and OVX groups. Glucose tolerance test (GTT) and Insulin tolerance test (ITT) revealed that S534A KI mice in OVX group were resistant to the glucose-lowering effect of insulin compared with WT mice. In addition, micro-computed tomography (μCT) showed that total bone mineral density was decreased in 4 weeks after OVX in both WT and S534A KI mice, which was more prominent in S534A KI mice. Bone morphometry analysis showed that the bone formation rate (BFR) was decreased and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts were increased in S534A KI mice OVX group, indicating that both bone formation and resorption were involved in the enhanced bone loss in KI OVX group. Furthermore, we found that mesenchymal stem cell (MSC) both from bone and adipose tissue in S534A KI mice were more likely to differentiate into adipocytes than in WT mice with the increased expression of PPAR-γ and C/EBP. BMSCs from S534A KI mice exhibited decreased differentiation potentiality into osteoblast compared with WT mice.
Taken together, these results indicated that S534A KI mice are subject to obesity and osteoporosis compared with WT mice under the condition of estrogen deficiency, suggesting that the regulation of NF-κB signaling by phosphorylation of S534 of p65 is involved in both postmenopausal obesity and osteoporosis.
We generated knock-in mice in which the activity of NF-κB signaling is enhanced, by expressing a mutant p65 with a serine-to-alanine substitution at position 534 (S534A KI mice). Wild-type (WT) and S534A KI mice were performed sham operation or ovariectomy (OVX) to mimic the estrogen deficiency condition and further maintained by normal diet for 12 weeks to analyze the systemic energy metabolism and bone metabolism.
We found that even though WT and S534A KI mice have similar daily food intake, S534A KI 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 S534A KI mice compared with WT mice in OVX group. Histological analysis showed adipocyte size of S534A KI mice was also larger than WT mice in both sham and OVX groups. Glucose tolerance test (GTT) and Insulin tolerance test (ITT) revealed that S534A KI mice in OVX group were resistant to the glucose-lowering effect of insulin compared with WT mice. In addition, micro-computed tomography (μCT) showed that total bone mineral density was decreased in 4 weeks after OVX in both WT and S534A KI mice, which was more prominent in S534A KI mice. Bone morphometry analysis showed that the bone formation rate (BFR) was decreased and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts were increased in S534A KI mice OVX group, indicating that both bone formation and resorption were involved in the enhanced bone loss in KI OVX group. Furthermore, we found that mesenchymal stem cell (MSC) both from bone and adipose tissue in S534A KI mice were more likely to differentiate into adipocytes than in WT mice with the increased expression of PPAR-γ and C/EBP. BMSCs from S534A KI mice exhibited decreased differentiation potentiality into osteoblast compared with WT mice.
Taken together, these results indicated that S534A KI mice are subject to obesity and osteoporosis compared with WT mice under the condition of estrogen deficiency, suggesting that the regulation of NF-κB signaling by phosphorylation of S534 of p65 is involved in both postmenopausal obesity and osteoporosis.