title: Increased Circulating Adiponectin in Response to Thiazolidinediones: Investigating the Role of Bone Marrow Adipose Tissue.
abstract: BACKGROUND
  Bone marrow adipose tissue (MAT) contributes to increased circulating adiponectin, an insulin-sensitizing hormone, during caloric restriction (CR), but whether this occurs in other contexts remains unknown. The antidiabetic thiazolidinediones (TZDs) also promote MAT expansion and hyperadiponectinemia, even without increasing adiponectin expression in white adipose tissue (WAT).
  
  
  OBJECTIVE
  To test the hypothesis that MAT expansion contributes to TZD-associated hyperadiponectinemia, we investigated the effects of rosiglitazone, a prototypical TZD, in wild-type (WT) orOcn-Wnt10b mice. The latter resist MAT expansion during CR, leading us to postulate that they would also resist this effect of rosiglitazone.
  
  
  METHODS
  Male and female WT orOcn-Wnt10b mice (C57BL/6J) were treated with or without rosiglitazone for 2, 4, or 8 weeks, up to 30 weeks of age. MAT content was assessed by osmium tetroxide staining and adipocyte marker expression. Circulating adiponectin was determined by ELISA.
  
  
  RESULTS
  In WT mice, rosiglitazone caused hyperadiponectinemia and MAT expansion. Compared to WT mice,Ocn-Wnt10b mice had significantly less MAT in distal tibiae and sometimes in proximal tibiae; however, interpretation was complicated by the leakage of osmium tetroxide from ruptures in some tibiae, highlighting an important technical consideration for osmium-based MAT analysis. Despite decreased MAT inOcn-Wnt10b mice, circulating adiponectin was generally similar between WT andOcn-Wnt10b mice; however, in females receiving rosiglitazone for 4 weeks, hyperadiponectinemia was significantly blunted inOcn-Wnt10b compared to WT mice. Notably, this was also the only group in which tibial adiponectin expression was lower than in WT mice, suggesting a close association between MAT adiponectin production and circulating adiponectin. However, rosiglitazone significantly increased adiponectin protein expression in WAT, suggesting that WAT contributes to hyperadiponectinemia in this context. Finally, rosiglitazone upregulated uncoupling protein 1 in brown adipose tissue (BAT), but this protein was undetectable in tibiae, suggesting that MAT is unlikely to share thermogenic properties of BAT.
  
  
  CONCLUSIONS
  TZD-induced hyperadiponectinemia is closely associated with increased adiponectin production in MAT but is not prevented by the partial loss of MAT that occurs inOcn-Wnt10b mice. Thus, more robust loss-of-MAT models are required for future studies to better establish MAT's elusive functions, both on an endocrine level and beyond.
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh , Edinburgh , UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sulston
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Learman
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Bofeng
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Scheller
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Sebastian D
authors.initials: SD
authors.lastname: Parlee
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Becky R
authors.initials: BR
authors.lastname: Simon
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bree
authors.affiliation: Department of Orthopaedics, University of Edinburgh , Edinburgh , UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wallace
authors.affiliation: Musculoskeletal Research, Lilly Research Laboratories , Indianapolis, IN , USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Ormond A
authors.initials: OA
authors.lastname: MacDougald
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Cawthorn
keywords: UCP1; adiponectin; beige adipocyte; bone marrow adipose tissue; brown adipose tissue; rosiglitazone; thiazolidinedione; white adipose tissue