Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes

Nat Med. 2015 Jul;21(7):760-8. doi: 10.1038/nm.3881. Epub 2015 Jun 15.

Abstract

Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / cytology
  • Adipocytes, Brown / metabolism*
  • Adipocytes, White / cytology
  • Adipocytes, White / metabolism*
  • Biomarkers / metabolism*
  • Cell Differentiation
  • Cell Line, Transformed
  • Cell Membrane / metabolism
  • Clone Cells
  • Gene Expression Profiling*
  • Genes, Reporter
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Integrin beta1 / metabolism
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Endothelin B
  • Receptors, Endothelin / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Thermogenesis / genetics*
  • Uncoupling Protein 1

Substances

  • Biomarkers
  • EDNRB protein, human
  • Guanine Nucleotide Exchange Factors
  • Integrin beta1
  • Ion Channels
  • Mitochondrial Proteins
  • PREX1 protein, human
  • RNA, Messenger
  • Receptor, Endothelin B
  • Receptors, Endothelin
  • UCP1 protein, human
  • Uncoupling Protein 1