title: Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton.
abstract: It is known that insulin resistance and type 2 diabetes mellitus are associated with increased fractures and that brown adipose tissue (BAT) counteracts many if not all of the symptoms associated with type 2 diabetes. By the use of FoxC2(AD)(+/Tg) mice, a well-established model for induction of BAT, or beige fat, we present data extending the beneficial action of beige fat to also include a positive effect on bone. FoxC2(AD)(+/Tg) mice are lean and insulin-sensitive and have high bone mass due to increased bone formation associated with high bone turnover. Inducible BAT is linked to activation of endosteal osteoblasts whereas osteocytes have decreased expression of the Sost transcript encoding sclerostin and elevated expression of Rankl. Conditioned media (CM) collected from forkhead box c2 (FOXC2)-induced beige adipocytes activated the osteoblast phenotype and increased levels of phospho-AKT and β-catenin in recipient cells. In osteocytes, the same media decreased Sost expression. Immunodepletion of CM with antibodies against wingless related MMTV integration site 10b (WNT10b) and insulin-like growth factor binding protein 2 (IGFBP2) resulted in the loss of pro-osteoblastic activity, and the loss of increase in the levels of phospho-AKT and β-catenin. Conversely, CM derived from cells overexpressing IGFBP2 or WNT10b restored osteoblastic activity in recipient cells. In conclusion, beige fat secretes endocrine/paracrine activity that is beneficial for the skeleton.
authors.affiliation: Departments of Orthopaedic Surgery, University ofToledo Health Sciences Campus, Toledo, OH 43614, USA.
authors.forename: Sima
authors.initials: S
authors.lastname: Rahman
authors.forename: Yalin
authors.initials: Y
authors.lastname: Lu
authors.forename: Piotr J
authors.initials: PJ
authors.lastname: Czernik
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: Sven
authors.initials: S
authors.lastname: Enerback
authors.forename: Beata
authors.initials: B
authors.lastname: Lecka-Czernik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D045930:Anabolic Agents / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D045930:Anabolic Agents; D017077:Culture Media, Conditioned; D051858:Forkhead Transcription Factors; D006023:Glycoproteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; C486030:Sost protein, mouse; C505689:Tnfsf11 protein, mouse; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D051176:beta Catenin; C082078:mesenchyme fork head 1 protein