摘要
Fibroblast growth factor 19(FGF19) functions as a hormone by affecting glucose metabolism. FGF19 improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. A functional cellular FGF19 receptor consists of FGF receptor(FGFR) and glycosaminoglycan complexed with either α Klotho or β Klotho. Interestingly, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar levels to a healthy range. FGF1 binds heparin with high affinity whereas FGF19 does not, indicating that polysaccharides other than heparin might enhance FGF19/FGFR signaling. Using a FGFs/FGFR1 c signaling-dependent Ba F3 cell proliferation assay, we discovered that polyguluronate sulfate(PGS) and its oligosaccharides, PGS12 and PGS25, but not polyguluronate(PG), a natural marine polysaccharide, enhanced FGF19/FGFR1 c signaling better than that of heparin based on ~3H-thymidine incorporation. Interestingly, PGS6, PGS8, PGS10, PGS12, PGS25, and PGS, but not PG, had comparable FGF1/FGFR1 c signal-stimulating activity compared to that of heparin. These results indicated that PGS and its oligosaccharides were excellent FGF1/FGFR1 c and FGF19/FGFR1 c signaling enhancers at cellular level. Since the inexpensive PGS and PGS oligosaccharides can be absorbed through oral route, these seaweed-derived compounds merit further investigation as novel agents for the treatment of type 2 diabetes through enhancing FGF1/FGFR1 c and FGF19/FGFR1 c signaling in future.
Fibroblast growth factor 19（FGF19） functions as a hormone by affecting glucose metabolism. FGF19 improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. A functional cellular FGF19 receptor consists of FGF receptor（FGFR） and glycosaminoglycan complexed with either α Klotho or β Klotho. Interestingly, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar levels to a healthy range. FGF1 binds heparin with high affinity whereas FGF19 does not, indicating that polysaccharides other than heparin might enhance FGF19/FGFR signaling. Using a FGFs/FGFR1 c signaling-dependent Ba F3 cell proliferation assay, we discovered that polyguluronate sulfate（PGS） and its oligosaccharides, PGS12 and PGS25, but not polyguluronate（PG）, a natural marine polysaccharide, enhanced FGF19/FGFR1 c signaling better than that of heparin based on ^3H-thymidine incorporation. Interestingly, PGS6, PGS8, PGS10, PGS12, PGS25, and PGS, but not PG, had comparable FGF1/FGFR1 c signal-stimulating activity compared to that of heparin. These results indicated that PGS and its oligosaccharides were excellent FGF1/FGFR1 c and FGF19/FGFR1 c signaling enhancers at cellular level. Since the inexpensive PGS and PGS oligosaccharides can be absorbed through oral route, these seaweed-derived compounds merit further investigation as novel agents for the treatment of type 2 diabetes through enhancing FGF1/FGFR1 c and FGF19/FGFR1 c signaling in future.
基金
supported by the National Natural Science Foundation of China (No. 91129706)
NSFC-Shandong Joint Fund (Nos. U1406402 and U1606403)
National Key Technology R & D Program of the Ministry of Science and Technology (No. 2013BAB01B02)
Taishan Scholar Special Fund of Shandong Province in China (G. Y. and L. Z.)
the Major Science and Technology Projects of Shandong Province (No. 2015 ZDJS04002)
