title: Biomarkers of browning of white adipose tissue and their regulation during exercise- and diet-induced weight loss.
abstract: BACKGROUND
  A hypothesis exists whereby an exercise- or dietary-induced negative energy balance reduces human subcutaneous white adipose tissue (scWAT) mass through the formation of brown-like adipocyte (brite) cells. However, the validity of biomarkers of brite formation has not been robustly evaluated in humans, and clinical data that link brite formation and weight loss are sparse.
  
  
  OBJECTIVE
  We used rosiglitazone and primary adipocytes to stringently evaluate a set of biomarkers for brite formation and determined whether the expression of biomarker genes in scWAT could explain the change in body composition in response to exercise training combined with calorie restriction in obese and overweight women (n = 79).
  
  
  METHODS
  Gene expression was derived from exon DNA microarrays and preadipocytes from obesity-resistant and -sensitive mice treated with rosiglitazone to generate candidate brite biomarkers from a microarray. These biomarkers were evaluated against data derived from scWAT RNA from obese and overweight women before and after supervised exercise 5 d/wk for 16 wk combined with modest calorie restriction (∼0.84 MJ/d).
  
  
  RESULTS
  Forty percent of commonly used brite gene biomarkers exhibited an exon or strain-specific regulation. No biomarkers were positively related to weight loss in human scWAT. Greater weight loss was significantly associated with less uncoupling protein 1 expression (P = 0.006, R(2) = 0.09). In a follow-up global analysis, there were 161 genes that covaried with weight loss that were linked to greater CCAAT/enhancer binding protein α activity (z = 2.0, P = 6.6 × 10(-7)), liver X receptor α/β agonism (z = 2.1, P = 2.8 × 10(-7)), and inhibition of leptin-like signaling (z = -2.6, P = 3.9 × 10(-5)).
  
  
  CONCLUSIONS
  We identify a subset of robust RNA biomarkers for brite formation and show that calorie-restriction-mediated weight loss in women dynamically remodels scWAT to take on a more-white rather than a more-brown adipocyte phenotype.
authors.affiliation: School of Medicine, Derby Royal Hospital, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Asif
authors.identifier: http://orcid.org/0000-0001-6201-0624
authors.initials: A
authors.lastname: Nakhuda
authors.affiliation: Department of Kinesiology, Brock University, St. Catharines, Canada;
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Josse
authors.affiliation: Royal Veterinary College, London, United Kingdom;
authors.forename: Valentina
authors.initials: V
authors.lastname: Gburcik
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, United Kingdom;
authors.forename: Hannah
authors.identifier: http://orcid.org/0000-0002-9009-3049
authors.initials: H
authors.lastname: Crossland
authors.affiliation: Functional Genomics, Nestle Institute of Health Sciences, Lausanne, Switzerland; and.
authors.forename: Frederic
authors.initials: F
authors.lastname: Raymond
authors.affiliation: Functional Genomics, Nestle Institute of Health Sciences, Lausanne, Switzerland; and.
authors.forename: Sylviane
authors.identifier: http://orcid.org/0000-0003-2434-8733
authors.initials: S
authors.lastname: Metairon
authors.affiliation: Royal Veterinary College, London, United Kingdom;
authors.forename: Liam
authors.initials: L
authors.lastname: Good
authors.affiliation: School of Medicine, Derby Royal Hospital, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Atherton
authors.affiliation: Exercise Metabolism Research Group, McMaster University, Hamilton, Canada.
authors.forename: Stuart M
authors.identifier: http://orcid.org/0000-0002-1956-4098
authors.initials: SM
authors.lastname: Phillips
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, United Kingdom; jamie.timmons@gmail.com.
authors.forename: James A
authors.identifier: http://orcid.org/0000-0002-2255-1220
authors.initials: JA
authors.lastname: Timmons
mesh_terms: D000069797:Adipocytes, Beige / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069796:Adipose Tissue, Beige / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004038:Diet, Reducing; D015444:Exercise; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D050177:Overweight / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D012333:RNA, Messenger / Q000378:metabolism*; D050151:Subcutaneous Fat / Q000378:metabolism / Q000473:pathology*; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss
chemical_list: D015415:Biomarkers; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D000071256:Uncoupling Protein 1
keywords: browning; exercise; microarray; obesity; weight loss; white adipose tissue