title: Thyroid hormone acting via TRβ induces expression of browning genes in mouse bone marrow adipose tissue.
abstract: OBJECTIVE
  Mutant hypothyroid mouse models have recently shown that thyroid hormone is critical for skeletal development during an important prepubertal growth period. Additionally, thyroid hormone negatively regulates total body fat, consistent with the well-established effects of thyroid hormone on energy and fat metabolism. Since bone marrow mesenchymal stromal cells differentiate into both adipocytes and osteoblasts and a relationship between bone marrow adipogenesis and osteogenesis has been predicted, we hypothesized thyroid hormone deficiency during the postnatal growth period increases marrow adiposity in mice.
  
  
  METHODS
  Marrow adiposity in TH-deficient (Tshr-/-) mice treated with T3/T4, TH receptor β-specific agonist GC-1, or vehicle control was evaluated via dual-energy X-ray absorptiometry and osmium micro-computed tomography. To further examine the mechanism for thyroid hormone regulation of marrow adiposity, we used real-time RT-PCR to measure the effects of thyroid hormone on adipocyte differentiation markers in primary mouse bone marrow mesenchymal stromal cells and two mouse cell lines in vitro and in Tshr-/-mice in vivo.
  
  
  RESULTS
  Marrow adiposity increased >20% (P < 0.01) in Tshr-/-mice at 3 weeks of age, and treatment with T3/T4 when serum thyroid hormone normally increases (day 5-14) rescued this phenotype. Furthermore, GC-1 rescued this phenotype equally well, suggesting this thyroid hormone effect is in part mediated via TRβ signaling. Treatment of bone marrow mesenchymal stromal or ST2 cells with T3 or GC-1 significantly increased expression of several brown/beige fat markers. Moreover, injection of T3/T4 increased browning-specific markers in white fat of Tshr-/-mice.
  
  
  CONCLUSIONS
  These data suggest that thyroid hormone regulation of marrow adiposity is mediated at least in part via activation of TRβ signaling.
authors.affiliation: Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA.|Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.|Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Lindsey
authors.affiliation: Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA. Subburaman.Mohan@va.gov.|Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA. Subburaman.Mohan@va.gov.|Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA. Subburaman.Mohan@va.gov.
authors.forename: Subburaman
authors.identifier: http://orcid.org/0000-0003-0063-986X
authors.initials: S
authors.lastname: Mohan
mesh_terms: D000085:Acetates / Q000494:pharmacology; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D051379:Mice; D018345:Mice, Knockout; D010636:Phenols / Q000494:pharmacology; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D013974:Thyroxine / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D000085:Acetates; C413355:GC 1 compound; D010636:Phenols; D011989:Receptors, Thyrotropin; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013974:Thyroxine
keywords: Adiposity; Bone density; Bone marrow stromal cells; Brown/beige fat; Obesity; Thyroid hormone; Thyroid hormone receptor beta