Neuropeptide Y (NPY), acting through hypothalamic Y2 receptors, is a powerful central regulator of bone mass as well as an essential coordinator of whole body energy balance. A sub-population of NPY neurons in the arcuate nucleus of the hypothalamus co-express agouti-related peptide (AgRP), and these neurons are indispensable for normal feeding behaviour. Recently, it was shown that impairing their function also led to reduced bone mass, an opposing phenotype to that seen in NPY and Y2 receptor deficient mice. Therefore, we sought to investigate whether NPY expression in these AgRP neurons is involved in their skeletal regulation.

We generated mice with selective deletion of NPY solely in AgRP neurons by crossing our NPY floxed mice with mice expressing Cre under control of the AgRP promotor. We then analysed their bone phenotype at 14 weeks of age using both DXA and µCT analysis. Interestingly, male AgRP^cre/+,NPY^f/f mice displayed significantly reduced femoral BMD and BMC compared to their littermate controls with no change in body weight or femur length. A more detailed analysis of their bone phenotype was performed by µCT and revealed a significant 40% reduction in trabecular BV/TV associated with a significant reduction in trabecular thickness. In addition, cortical bone volume and cortical thickness were significantly decreased.

The osteopenic bone phenotype observed in AgRP^cre/+,NPY^f/f mice recapitulates that seen in mice with impaired AgRP function and suggests that NPY mediates the action of AgRP on bone mass. Interestingly, this phenotype is in contrast to the anabolic bone phenotype observed in germline NPY-deficient mice. Thus, these data suggest that there are differing populations of NPY neurons with opposing functions in regards to the central control of bone mass and highlight the complex nature of NPY regulation of the skeleton.