Bone Abstracts

Rationale: Mice deficient in osteocalcin show an impaired glucose tolerance, however, the exact mechanism involved have yet to be fully elucidated. We aimed to overexpress osteocalcin to determine its effect on glucose homeostasis and explore the signalling pathway involved. We wished to expand upon previous preliminary data suggesting that this pathway involve neuropeptide Y (NPY) signalling.

Objective: To analyse the in vivo and in vitro phenotype of three transgenic models over expressing osteocalcin: i) OcnCre/Ocntg- in osteocalcin-producing cells (osteoblasts/ osteocytes), ii) NPYCre/Ocntg- in NPY expressing cells (hypothalamus, SNS, osteoblasts) and iii) PanCre/Ocntg- in all cells.

Methods and results: Glucose tolerance tests demonstrated that increased osteocalcin expression improves glucose tolerance. At 10 weeks, OcnCre/Ocntg displayed a significant increase in glucose tolerance; however this difference was lost as mice age. In OcnCre/Ocntg serum osteocalcin levels were slightly elevated at 16 weeks (mean (S.D.), ng/ul control 35.2(1), NPYCre/Ocntg 38.7(2), P<0.05), however, glucose tolerance was not different at this age, or at 22 weeks. In NPYCre/Ocntg, the more ‘neural’ model, improved glucose tolerance was maintained in 15-week-old mice, without change in serum osteocalcin (mean (S.D.), ng/ul control 39.0(2), NPYCre/Ocntg 35.1(2), ns). Interestingly, all transgenic models displayed powerful suppression of osteocalcin protein production, despite increased osteocalcin expression by the transgene. This was confirmed in PanCre/Ocntg, which did not display an increase in serum osteocalcin at 15 weeks, (mean (S.D.), ng/ul control 38.1(1), PanCre/Ocntg 35.1(2), ns), despite a marked increase in expression in non-skeletal tissues, and no increase in osteoblastic osteocalcin protein despite greater expression in primary osteoblastic cultures. This suppression of protein production attenuated any long-term changes in glucose tolerance.

Conclusions: These data indicate that osteocalcin released from bone cells is involved in modulating glucose homeostasis. Osteocalcin within NPY expressing cells increases the glucose modulatory effect, without a circulatory circuit, suggesting the potential for direct signalling of osteocalcin in neural cells. Osteocalcin protein production is powerfully limited in an anatomical, temporal and differentiation-specific manner.