title: Leptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism.
abstract: Leptin, the protein product of the ob gene, is essential for normal bone growth, maturation and turnover. Peripheral actions of leptin occur at lower serum levels of the hormone than central actions because entry of leptin into the central nervous system (CNS) is limited due to its saturable transport across the blood-brain barrier (BBB). We performed a study in mice to model the impact of leptin production associated with different levels of adiposity on bone formation and compared the response with well-established centrally mediated actions of the hormone on energy metabolism. Leptin was infused (0, 4, 12, 40, 140 or 400 ng/h) for 12 days into 6-week-old female ob/ob mice (n = 8/group) using sc-implanted osmotic pumps. Treatment resulted in a dose-associated increase in serum leptin. Bone formation parameters were increased at EC50infusion rates of 7-17 ng/h, whereas higher levels (EC50, 40-80 ng/h) were required to similarly influence indices of energy metabolism. We then analyzed gene expression in tibia and hypothalamus at dose rates of 0, 12 and 140 ng/h; the latter dose resulted in serum leptin levels similar to WT mice. Infusion with 12 ng/h leptin increased the expression of genes associated with Jak/Stat signaling and bone formation in tibia with minimal effect on Jak/Stat signaling and neurotransmitters in hypothalamus. The results suggest that leptin acts peripherally to couple bone acquisition to energy availability and that limited transport across the BBB insures that the growth-promoting actions of peripheral leptin are not curtailed by the hormone's CNS-mediated anorexigenic actions.
authors.affiliation: Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Philbrick
authors.affiliation: Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Wong
authors.affiliation: Biostatistics ProgramSchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Branscum
authors.affiliation: Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA.|Center for Healthy Aging ResearchOregon State University, Corvallis, Oregon, USA.
authors.forename: Russell T
authors.initials: RT
authors.lastname: Turner
authors.affiliation: Skeletal Biology LaboratorySchool of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA urszula.iwaniec@oregonstate.edu.|Center for Healthy Aging ResearchOregon State University, Corvallis, Oregon, USA.
authors.forename: Urszula T
authors.initials: UT
authors.lastname: Iwaniec
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D013977:Tibia / Q000187:drug effects / Q000378:metabolism
chemical_list: D020738:Leptin
keywords: animal model; bone formation; bone histomorphometry; neuroendocrine; osteoblasts