title: Uncoupling protein-1 is protective of bone mass under mild cold stress conditions.
abstract: Brown adipose tissue (BAT), largely controlled by the sympathetic nervous system (SNS), has the ability to dissipate energy in the form of heat through the actions of uncoupling protein-1 (UCP-1), thereby critically influencing energy expenditure. Besides BAT, the SNS also strongly influences bone, and recent studies have demonstrated a positive correlation between BAT activity and bone mass, albeit the interactions between BAT and bone remain unclear. Here we show that UCP-1 is critical for protecting bone mass in mice under conditions of permanent mild cold stress for this species (22°C). UCP-1-/-mice housed at 22°C showed significantly lower cancellous bone mass, with lower trabecular number and thickness, a lower bone formation rate and mineralising surface, but unaltered osteoclast number, compared to wild type mice housed at the same temperature. UCP-1-/-mice also displayed shorter femurs than wild types, with smaller cortical periosteal and endocortical perimeters. Importantly, these altered bone phenotypes were not observed when UCP-1-/-and wild type mice were housed in thermo-neutral conditions (29°C), indicating a UCP-1 dependent support of bone mass and bone formation at the lower temperature. Furthermore, at 22°C UCP-1-/-mice showed elevated hypothalamic expression of neuropeptide Y (NPY) relative to wild type, which is consistent with the lower bone formation and mass of UCP-1-/-mice at 22°C caused by the catabolic effects of hypothalamic NPY-induced SNS modulation. The results from this study suggest that during mild cold stress, when BAT-dependent thermogenesis is required, UCP-1 activity exerts a protective effect on bone mass possibly through alterations in central NPY pathways known to regulate SNS activity.
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Nguyen
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Lee
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Natalie K Y
authors.initials: NKY
authors.lastname: Wee
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ronaldo F
authors.initials: RF
authors.lastname: Enriquez
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ee Cheng
authors.initials: EC
authors.lastname: Khor
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Nie
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Sainsbury
authors.affiliation: Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of NSW, Kensington, Sydney, NSW 2052, Australia. Electronic address: h.herzog@garvan.org.au.
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002153:Calorimetry, Indirect; D003080:Cold Temperature; D004734:Energy Metabolism / Q000502:physiology; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D009478:Neuropeptide Y; D000071256:Uncoupling Protein 1
keywords: Bone; Brown adipose tissue; Cold stress; Energy homeostasis; Neuropeptide Y; Uncoupling protein-1