NPY signalling in osteoblasts controls glucose homeostasis in mice through an osteoglycin mediated mechanism
The skeleton has recently emerged as an additional player in the control of wholebody glucose metabolism; however, the mechanism behind this is not clear. Here we show that mice lacking neuropeptide Y, Y1 receptors solely in cells of the osteoblastic lineage (Y1f3.6Cre), not only have a high bone mass phenotype, but importantly also display altered glucose homeostasis. Y1f3.6Cre mice display significantly decreased pancreas weight, islet number and pancreatic insulin content leading to elevated glucose levels and reduced glucose tolerance, but with no effect on insulin induced glucose clearance. The reduced glucose tolerance and elevated bone mass was corrected in Y1f3.6Cre mice by bone marrow transplant from wildtype animals, reinforcing the osteoblastic nature of this pathway. Conditioned media from Y1f3.6Cre osteoblastic cultures was unable to stimulate insulin expression in MIN6 cells compared to conditioned media from wildtype osteoblast, indicating a direct signalling pathway. A comparison of wildtype and Y1f3.6Cre osteoblasts using microarray and mass spectrometry revealed the downregulation of osteoglycin, a secreted proteoglycan, in Y1f3.6Cre cells. Osteoglycin induced insulin expression in MIN6 cells and when injected intraperitonally, dose-dependently improved glucose tolerance. Mechanistically, this is mediated through synergistic enhancement of insulin action via significant upregulation of pAKT in muscle. Taken together, this identifies osteoglycin as a novel osteoblast-derived regulator of pancreas function and insulin secretion and illustrates a mechanism by which NPY signalling in bone tissue is capable of regulating glucose homeostasis.
|Authors||Lee, N.J.; Zhang, L.; Nguyen, A.D.; Enriquez, R.F.; Luzuriaga, J.; Ali, N.; Bensellam, M.; Lee, I-C.J.; Rogers, M.; Laybutt, R.; Baldock, P.A.; Herzog, H.|
|Publisher Name||NAT MED|
|Published Date||2015-03-01 00:00:00|