title: Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasis.
abstract: Insulin signaling in osteoblasts regulates global energy balance by stimulating the production of osteocalcin, a bone-derived protein that promotes insulin production and action. To identify the signaling pathways in osteoblasts that mediate insulin's effects on bone and energy metabolism, we examined the function of the tuberous sclerosis 2 (Tsc2) protein, a key target important in coordinating nutrient signaling. Here, we show that loss of Tsc2 in osteoblasts constitutively activates mTOR and destabilizes Irs1, causing osteoblasts to differentiate poorly and become resistant to insulin. Young Tsc2 mutant mice demonstrate hypoglycemia with increased levels of insulin and undercarboxylated osteocalcin. However, with age, Tsc2 mutants develop metabolic features similar to mice lacking the insulin receptor in the osteoblast, including peripheral adiposity, hyperglycemia, and decreased pancreatic β cell mass. These metabolic abnormalities appear to result from chronic elevations in undercarboxylated osteocalcin that lead to downregulation of the osteocalcin receptor and desensitization of the β cell to this hormone. Removal of a single mTOR allele from the Tsc2 mutant mice largely normalizes the bone and metabolic abnormalities. Together, these findings suggest that Tsc2 serves as a key checkpoint in the osteoblast that is required for proper insulin signaling and acts to ensure normal bone acquisition and energy homeostasis.
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Riddle
authors.forename: Julie L
authors.initials: JL
authors.lastname: Frey
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Tomlinson
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: DiGirolamo
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Faugere
authors.forename: Mehboob A
authors.initials: MA
authors.lastname: Hussain
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000502:physiology*; D015675:Osteocalcin / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D055114:X-Ray Microtomography
chemical_list: D007328:Insulin; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D015675:Osteocalcin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose