Hypothalamic Control of Bone Formation: Distinct Actions of Leptin and Y2 Receptor Pathways

Abstract

Leptin and Y2 receptors on hypothalamic NPY neurons mediate leptin effects on energy homeostasis; however, their interaction in modulating osteoblast activity is not established. Here, direct testing of this possibility indicates distinct mechanisms of action for leptin anti-osteogenic and Y2 −/− anabolic pathways in modulating bone formation.Introduction: Central enhancement of bone formation by hypothalamic neurons is observed in leptin-deficient ob/ob and Y2 receptor null mice. Similar elevation in central neuropeptide Y (NPY) expression and effects on osteoblast activity in these two models suggest a shared pathway between leptin and Y2 receptors in the central control of bone physiology. The aim of this study was to test whether the leptin and Y2 receptor pathways regulate bone by the same or distinct mechanisms. Materials and Methods:The interaction of concomitant leptin and Y2 receptor deficiency in controlling bone was examined in Y2 −/− ob/ob double mutant mice, to determine whether leptin and Y2 receptor deficiency have additive effects. Interaction between leptin excess and Y2 receptor deletion was examined using recombinant adeno-associated viral vector overproduction of NPY (AAV-NPY) to produce weight gain and thus leptin excess in adult Y2 −/− mice. Cancellous bone volume and bone cell function were assessed. Results: Osteoblast activity was comparably elevated in ob/ob, Y2

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

“…Consistent with this, a generalised exposure of central tissues to a KOR agonist induced neural activity in the Arc, a region of the hypothalamus that is known to regulate bone mass (Baldock et al, 2002;Elefteriou et al, 2003). Moreover, intra-nuclear injection of kappa agonist specifically into the Arc increase in NPY expression producing a powerful inhibition of osteoblast activity and reduction in bone mass (Baldock et al, 2005 andBaldock et al, 2009). Furthermore, a reduction in NPY signaling, as evident in Dyn−/− mice (Baldock et al, 2005, Baldock et al, 2009, Baldock et al, 2002, is associated with greater bone mass and osteoblast activity and calculated bone strength.…”

“…4D and E) or saline injected control groups. This clearly indicates that dynorphin signaling through its preferred kappa receptor increases NPY expression, which has been shown to result in decreased bone formation (Baldock et al, 2002(Baldock et al, , 2005 kappa opioid receptor expression, sustained activation of P-ERK is evident in neuronal cells, however activation of ERK phosphorylation was virtually absent in osteoblastic cells (Fig. 3C).…”

“…Both bone formation and bone resorption were increased, with osteoclasts being more common on bone surfaces in DynÀ/ À mice. Critically, bone formation was increased to a greater degree than bone resorption, with increases in the rate at which shown to result in decreased bone formation ( Baldock et al, 2002, Baldock et al, 2005 3.6. Bone homeostasis following coincident loss of dynorphin and neuropeptide Y signaling The involvement of NPY-mediated processes in the skeletal phenotype of Dyn−/− mice was further explored by comparison of Dyn−/− with NPY−/− mice and Dyn−/−NPY−/− double delete mice.…”

“…Importantly, alterations in hypothalamic NPY, acting through the Arc, have previously been demonstrated to exert powerful effects upon bone mass and osteoblast activity. Arcuate-specific elevation of NPY expression induces marked reduction in osteoblast activity (Baldock et al, 2005) and acted to correct the increased bone mass following germline NPY ablation (Baldock et al, 2009). The relationship between opioid signaling and NPY was clearly demonstrated in feeding studies with NPYinduced feeding being dose-dependently reduced by pretreatment with kappa opioid receptor antagonist or kappa antisense probes (Israel et al, 2005), demonstrating the downstream actions of dynorphin signaling in mediating NPY effects on feeding.…”

“…We have shown previously that lack of dynorphin signaling leads to reduced expression of neuropeptide Y in the Arc (Sainsbury et al, 2007 andWittmann et al, 2009), which would be expected to result in a NPY-induced increase in bone mass and provide a mechanism for dynorphins action on bone (Baldock et al, 2005, Baldock et al, 2009, Baldock et al, 2002. In order to test this hypothesis we injected KOR (U-50,488), DOR (DPDPE) and MOR (DAMGO) receptor-specific agonists unilaterally into the arcuate nucleus of wild type mice and measured changes in NPY mRNA expression by in situ hybridization between injected and contralateral sides of the Arc.…”