The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known.
Researchers generated multiple lines of mice to affect AgRP (agouti-related peptide) neuronal circuit integrity. They found that mice with Ucp2 (uncoupling protein 2) gene deletion, in which AgRP neuronal function was impaired, were osteopenic.
This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of histone deacetylase, sirtuin 1 (AgRP-Sirt1−/−), mice also developed reduced bone mass.
No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1−/− mice reversed osteopenia in transgenic animals.
Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action.