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Title: An age-dependent interaction with leptin unmasks ghrelin's bone-protective effects

Author
item VAN DER VELDE, MARTIJN - Erasmus University
item VEN DER EERDEN, BRAM CJ - Erasmus University
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)
item ALMERING, JULIA MM - Erasmus University
item VAN DER LELY, AART-JAN - Erasmus University
item DELHANTY, PATRIC JD - Erasmus University
item SMITH, ROY - Scripps Institute

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/25/2012
Publication Date: 6/14/2012
Citation: Van Der Velde, M., Ven Der Eerden, B., Sun, Y., Almering, J., Van Der Lely, A., Delhanty, P., Smith, R.G., Van Leeuwen, J. 2012. An age-dependent interaction with leptin unmasks ghrelin's bone-protective effects. Endocrinology. 153(8):3593-3602.

Interpretive Summary: The hormones ghrelin and leptin have opposite effects on energy balance: ghrelin stimulates appetite while leptin inhibits it. Ghrelin functions through its receptor. It is unknown whether ghrelin and leptin antagonize each other's effects on bone. We have studied genetically altered mice that are missing either the ghrelin receptor or hormonal leptin, or both the ghrelin receptor and hormonal leptin. Our data show that ghrelin has dual benefits on bone cells, stimulating its growth and inhibiting its breakdown. Interestingly, leptin eliminates the protective effects of ghrelin on bone, indicating that ghrelin and leptin have opposite effects on bone. We have also observed that ghrelin's protective effect on bone is lost during aging, which suggests that ghrelin's protective effect is important for preventing age-associated bone loss. Thus, ghrelin may be a promising therapy for bone loss. Increasing ghrelin levels or improving its efficiency may be beneficial in preventing/treating age-associated bone loss.

Technical Abstract: The mutual interplay between energy homeostasis and bone metabolism is an important emerging concept. Ghrelin and leptin antagonize each other in regulating energy balance, but the role of this interaction in bone metabolism is unknown. Using ghrelin receptor and leptin-deficient mice, we show that ghrelin has dual effects on osteoclastogenesis, inhibiting osteoclast progenitors directly and stimulating osteoclastogenesis via a more potent systemic/central pathway. Using mice with combined ghrelin receptor and leptin deficiency, we find that this systemic osteoclastogenic activity is suppressed by leptin, thus balancing the two counterregulatory ghrelin pathways and leading to an unchanged bone structure. With aging, this osteoclastogenic ghrelin pathway is lost, unmasking the direct protective effect of ghrelin on bone structure. In conclusion, we identify a novel regulatory network linking orexigenic and anorectic metabolic factors with bone metabolism that is age dependent.