Modulation of glucose and lipid metabolism, and osteogenesis by adiponectin signaling

• Main Authors: Yuan-Yu Lin, 林原佑
• Other Authors: 丁詩同
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/19150765557677741037

博士 === 國立臺灣大學 === 動物科學技術學研究所 === 103 === Adiponectin and its receptors have been demonstrated to play important roles in regulating glucose and lipid metabolism in mice. Obesity, type II diabetes and cardiovascular diseases are tightly correlated with down-regulation of adiponectin signaling. Our AdipoR1 transgenic mice with fluorescent proteins serve as a great model to investigate the involvement of adiponectin signaling in the biological processes. Mice overexpressing porcine adiponectin receptor 1 (pAdipoR1) fed with high fat/high sucrose diet for 24 weeks, exhibited no change in weight gain and demonstrated amelioration of insulin resistance. In this current study, we isolated the mesenchymal stem cells from wild-type (WT-MSC) and adiponectin receptor 1-transgenic mice (pR1-tMSC) and transplanted the cells into the diet-induced obese (DIO) mice, which exhibited diabetic and insulin insensitive. After once-a-week cell transplantation for 8 weeks, WT-MSC and pR1-tMSC treatments improved fatty acid oxidation and alleviate lipid accumulation in the liver, with pR1-tMSC further enhancing glucose metabolism in DIO mice. Our current study, for the first time, demonstrated therapeutic application of pR1-tMSC to improve diet-induced metabolic complications. Metabolic syndrome and aging - associated osteoporosis and metabolic bone diseases is also an active field in recent years. Adiponectin and its receptors are expressed in bone marrow-derived osteoblasts. We used pAdipoR1 transgenic mice as a model to evaluate the role of AdipoR1 on bone physiology at different ages. pAdipoR1 transgenic mice had higher bone mineral density than wild-type mice in both genders at 56 weeks of age. The bone volume and trabecular number, measured by micro-computed tomography (μCT) were significantly greater in transgenic mice than those of wild-type female mice at both 8 and 56 weeks of age. ELISA analysis revealed that both serum osteocalcin and osteoprotegerin (OPG) were significantly increased in 8-week old pAdipoR1 transgenic mice of both genders. Furthermore, serum OPG was elevated at 32 and 56 weeks of age pAdipoR1 transgenic mice of both sex. Serum TRAP5b concentration was reduced in 8 and 56 weeks old male pAdipoR1 mice compared with wild-type male mice. Knock-down of AdipoR1 significantly decreased gene expression of osteocalcin, OPG, alkaline phosphatase and msh homeobox 2 and suppressed the mineralization in MC3T3-E1 cells and mesenchymal stem cells. In addition, pathscan analysis, and real-time PCR analysis suggested AdipoR1 regulates osteoblast differentiation through GSK-3 β and β-Catenin signaling. Consequently, the lack of AdipoR1 impaired osteoblast differentiation and bone formation. We concluded that AdipoR1 is a critical factor for the osteoblast differentiation and bone homeostasis.