title: 1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration.
abstract: OBJECTIVE
  The vitamin D system plays a role in metabolism regulation. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) suppressed 3T3-L1 white adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure, whereas mice with adipose-specific VDR over-expression showed decreased energy expenditure. Brown adipose tissue (BAT), now known to be present in adult humans, functions in non-shivering thermogenesis by uncoupling ATP synthesis from respiration and plays an important role in energy expenditure. However, the effects of 1,25(OH)2D3/VDR on brown adipocyte differentiation and mitochondrial respiration have not been reported.
  
  
  METHODS
  mRNA expression of VDR and the metabolizing enzymes 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) were examined in BAT of mice models of obesity and during brown adipocyte differentiation. The effects of 1,25(OH)2D3 and VDR over-expression on brown adipocyte differentiation and functional outcomes were evaluated.
  
  
  RESULTS
  No significant changes in mRNA of VDR and CYP27B1 were noted in both diet-induced obese (DIO) and ob/ob mice, whereas uncoupling protein 1 mRNA was downregulated in BAT of ob/ob, but not DIO mice when compared to the controls. In contrast, mRNA of VDR, CYP24A1, and CYP27B1 were downregulated during brown adipocyte differentiation in vitro. 1,25(OH)2D3 dose-dependently suppressed brown adipocyte differentiation, accompanied by suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak. Consistently, over-expression of VDR also suppressed brown adipocyte differentiation. Further, both 1,25(OH)2D3 and VDR over-expression suppressed PPARγ transactivation in brown preadipocytes.
  
  
  CONCLUSIONS
  Our results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration. The role of 1,25(OH)2D3/VDR system in regulating BAT development and function in obesity warrant further investigation.
authors.affiliation: Department of Nutrition, University of Tennessee, 1215 W. Cumberland Ave, Knoxville, TN, 37996, USA.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Ricciardi
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Bae
authors.forename: Debora
authors.initials: D
authors.lastname: Esposito
authors.forename: Slavko
authors.initials: S
authors.lastname: Komarnytsky
authors.forename: Pan
authors.initials: P
authors.lastname: Hu
authors.forename: Jiangang
authors.initials: J
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D052437:Adipocytes, Brown / Q000502:physiology* / Q000648:ultrastructure; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D004734:Energy Metabolism; D015870:Gene Expression; D007473:Ion Channels / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics; D009765:Obesity / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology*; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D000071256:Uncoupling Protein 1; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol