A Reservoir of Brown Adipocyte Progenitors in Human Skeletal Muscle

Abstract

Brown adipose tissue uncoupling protein-1 (UCP1) plays a major role in the control of energy balance in rodents. It has long been thought, however, that there is no physiologically relevant UCP1 expression in adult humans. In this study we show, using an original approach consisting of sorting cells from various tissues and differentiating them in an adipogenic medium, that a stationary population of skeletal muscle cells expressing the CD34 surface protein can differentiate in vitro into genuine brown adipocytes with a high level of UCP1 expression and uncoupled respiration. These cells can be expanded in culture, and their UCP1 mRNA expression is strongly increased by cell-permeating cAMP derivatives and a peroxisome-proliferator-activated receptor-␥ (PPAR␥) agonist. Furthermore, UCP1 mRNA was detected in the skeletal muscle of adult humans, and its expression was increased in vivo by PPAR␥ agonist treatment. All the studies concerning UCP1 expression in adult humans have until now been focused on the white adipose tissue. Here we show for the first time the existence in human skeletal muscle and the prospective isolation of progenitor cells with a high potential for UCP1 expression. The discovery of this reservoir generates a new hope of treating obesity by acting on energy dissipation.

Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

“…Myf5-expressing progenitors can give rise to both skeletal muscle and interscapular brown fat (13). In accordance with these observations, brown-fat progenitors have also been identified in human skeletal muscle (14). However, not all brown-fat cells are derived from myf5-expressing progenitors.…”

Ontogenesis of muscle and adipose tissues and their interactions in ruminants and other species

“…In addition, consistent with a common muscle and BAT progenitor, other groups have reported that (i) BAT and skeletal muscle are derived from a common progenitor in the dermomyotome (Atit et al, 2006), (ii) myogenin-deficient neonatal mice not only have impaired muscle development but also exhibit an accumulation of brown adipocytes in the anatomical location of muscles (Hasty et al, 1993) and (iii) brown but not white adipose precursors express many genes and microRNA specific to muscle precursors (Timmons et al, 2007). Finally, adult skeletal muscle has been shown to be a 'reservoir' of brown adipocyte progenitors in humans (Crisan et al, 2008) and mice (Almind et al, 2007). Whether a single Myf51 cell gives rise to both BATand muscle, or whether there are distinct populations of Myf51 progenitors remains unknown.…”

Brown adipocyte progenitor population is modified in obese and diabetic skeletal muscle

“…8 We also reported the existence of low levels of UCP1 mRNA in human muscle biopsies suggesting the presence of mature brown adipocytes in adult skeletal muscle. 8 As transgenic expression of UCP1 in muscle is known to increase insulin-mediated glucose uptake, 9 human skeletal muscle brown adipocytes might protect not only from obesity but also from insulin resistance.…”

“…8 Cyclophilin A was used as a control to account for any variations due to the efficiency of the reverse transcription. The upstream and downstream oligonucleotide primers were chosen on both sides of an intron to prevent amplification of contaminating genomic DNA.…”

“…These UCP1 primers have previously been shown to amplify the UCP1 gene in human muscle tissue. 8 CD34 upstream 5 0 -TGAAATTGACTCAGGGCATCTG-3 0 and downstream 5 0 -CCTCTC CCCTGTCCTTCTTAAAC-3 0 , nucleotides 548-623 of CD34 cDNA (NM_001025109 isoform a).…”