title: Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice.
abstract: Starvation induces low bone mass and high bone marrow adiposity in humans, but the underlying mechanisms are poorly understood. The adipokine leptin falls in starvation, suggesting that hypoleptinemia may be a link between negative energy balance, bone marrow fat accumulation, and impaired skeletal acquisition. In that case, treating mice with leptin during caloric restriction (CR) should reduce marrow adipose tissue (MAT) and improve bone mass. To test this hypothesis, female C57Bl/6J mice were fed a 30% CR or normal (N) diet from 5 to 10 weeks of age, with daily injections of vehicle (VEH), 1mg/kg leptin (LEP1), or 2mg/kg leptin (LEP2) (N=6-8/group). Outcomes included body mass, body fat percentage, and whole-body bone mineral density (BMD) via peripheral dual-energy X-ray absorptiometry, cortical and trabecular microarchitecture via microcomputed tomography (μCT), and MAT volume via μCT of osmium tetroxide-stained bones. Overall, CR mice had lower body mass, body fat percentage, BMD, and cortical bone area fraction, but more connected trabeculae, vs N mice (P<0.05 for all). Most significantly, although MAT was elevated in CR vs N overall, leptin treatment blunted MAT formation in CR mice by 50% vs VEH (P<0.05 for both leptin doses). CR LEP2 mice weighed less vs CR VEH mice at 9-10 weeks of age (P<0.05), but leptin treatment did not affect body fat percentage, BMD, or bone microarchitecture within either diet. These data demonstrate that once daily leptin bolus during CR inhibits bone marrow adipose expansion without affecting bone mass acquisition, suggesting that leptin has distinct effects on starvation-induced bone marrow fat formation and skeletal acquisition.
authors.affiliation: Department of AnthropologyUniversity of Michigan, Ann Arbor, Michigan, USA mjdevlin@umich.edu.
authors.forename: M J
authors.initials: MJ
authors.lastname: Devlin
authors.affiliation: Center for Advanced Orthopedic StudiesBeth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: Center for Advanced Orthopedic StudiesBeth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Conlon
authors.affiliation: Center for Advanced Orthopedic StudiesBeth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: M van
authors.initials: Mv
authors.lastname: Vliet
authors.affiliation: Center for Advanced Orthopedic StudiesBeth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: L
authors.initials: L
authors.lastname: Louis
authors.affiliation: Maine Medical Center Research InstituteScarborough, Maine, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Rosen
authors.affiliation: Center for Advanced Orthopedic StudiesBeth Israel Deaconess Medical Center, Boston, Massachusetts, USA Harvard Medical SchoolBoston, Massachusetts, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Bouxsein
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects*; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects; D031204:Caloric Restriction / Q000009:adverse effects*; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006801:Humans; D020738:Leptin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage; D055114:X-Ray Microtomography
chemical_list: D020738:Leptin; D011994:Recombinant Proteins
keywords: bone; caloric restriction; leptin; marrow adiposity; mouse