title: Functional thermogenic beige adipogenesis is inducible in human neck fat.
abstract: BACKGROUND
  Recent studies suggest human neck brown adipose tissue (BAT) to consist of 'brown adipocyte (BA)-like' or beige adipocytes. However, little is known about their thermogenic function. Within the beige adipocyte transcriptome, fibroblast growth factor-21 (FGF21) is a gene whose protein product acts as an adipokine, regulating cold-induced thermogenesis in animals. Here, we explored (i) the adipogenic potential, thermogenic function and FGF21 secretory capacity of beige adipocytes derived from human neck fat and (ii) the role of FGF21 in modulating adipose bioenergetics.
  
  
  METHODS
  Progenitors isolated from human cervical fat were differentiated into adipocytes with either a BA-like or white adipocyte (WA) phenotype. FGF21 secretion was measured by enzyme-linked immuosorbent assay. Real-time PCR/western blotting was used to determine cellular mRNA/protein levels. Extracellular flux bioanalyzer was used to quantify adipocyte oxygen consumption and fatty acid oxidation. Adipocyte heat production was measured by infrared thermography.
  
  
  RESULTS
  Under hormonal manipulation, primary human neck pre-adipocytes differentiated into adipocytes with either BA-like or WA phenotypes, on gene/protein and functional levels. BA-like cells expressed beige but not classic BA markers. During BA differentiation, FGF21 gene expression and secretion were increased, and were augmented following norepinephrine exposure (a cold mimic in vitro). Differentiated WA expressed β-klotho, a critical co-factor mediating FGF21 action. Treatment of WA with FGF21-induced UCP1 expression and increased oxygen consumption, respiratory uncoupling, norepinephrine-mediated thermogenesis, fatty acid oxidation and heat production, thus recapitulating the association between cold-induced FGF21 secretion and cold-induced thermogenesis in vivo.
  
  
  CONCLUSIONS
  Beige adipocytes are thermogenic in humans. FGF21 is a beige adipokine capable of promoting a brown fat-like thermogenic program in WAs.
  
  
  CONCLUSIONS
  This study provides first evidence of inducible functional thermogenic beige adipogenesis in human neck fat. FGF21 holds promise as a cold-induced beige adipokine with metabolic benefits of therapeutic relevance through browning of white adipose tissue.
authors.affiliation: Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Lee
authors.affiliation: Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Werner
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kebebew
authors.affiliation: Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: F S
authors.initials: FS
authors.lastname: Celi
mesh_terms: D000222:Adaptation, Physiological; D052437:Adipocytes, Brown / Q000378:metabolism*; D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003080:Cold Temperature; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D022722:Thermogenesis; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors