title: Deficiency of the bone mineralization inhibitor NPP1 protects mice against obesity and diabetes.
abstract: The emergence of bone as an endocrine regulator has prompted a re-evaluation of the role of bone mineralization factors in the development of metabolic disease. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) controls bone mineralization through the generation of pyrophosphate, and levels of NPP1 are elevated both in dermal fibroblast cultures and muscle of individuals with insulin resistance. We investigated the metabolic phenotype associated with impaired bone metabolism in mice lacking the gene that encodes NPP1 (Enpp1(-/-) mice). Enpp1(-/-) mice exhibited mildly improved glucose homeostasis on a normal diet but showed a pronounced resistance to obesity and insulin resistance in response to chronic high-fat feeding. Enpp1(-/-) mice had increased levels of the insulin-sensitizing bone-derived hormone osteocalcin but unchanged insulin signalling within osteoblasts. A fuller understanding of the pathways of NPP1 could inform the development of novel therapeutic strategies for treating insulin resistance.
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian, Edinburgh, EH25 9RG, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Huesa
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian, Edinburgh, EH25 9RG, UK. dongxing.zhu@roslin.ed.ac.uk.
authors.forename: Dongxing
authors.initials: D
authors.lastname: Zhu
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian, Edinburgh, EH25 9RG, UK.
authors.forename: James D
authors.initials: JD
authors.lastname: Glover
authors.affiliation: Integrative and Molecular Physiology Research Unit Institut de Recherches Cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest - Laboratory 2750, Montréal, QC H2W 1R7, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
authors.affiliation: Department of Developmental Genetics, Columbia University, NY 10032, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian, Edinburgh, EH25 9RG, UK.
authors.forename: Elspeth M
authors.initials: EM
authors.lastname: Milne
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millan
authors.affiliation: Developmental Medicine, University of Glasgow, Glasgow, G12 8QQ, UK.
authors.forename: S Faisal
authors.initials: SF
authors.lastname: Ahmed
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian, Edinburgh, EH25 9RG, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Farquharson
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian, Edinburgh, EH25 9RG, UK.
authors.forename: Vicky E
authors.initials: VE
authors.lastname: MacRae
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000737:chemistry; D006706:Homeostasis; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000502:physiology*; D011755:Pyrophosphatases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D015675:Osteocalcin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D005947:Glucose
keywords: Diabetes; Mineralization; NPP1; Obesity