MicroRNAs regulate human adipocyte lipolysis: effects of miR-145 are linked to TNF-α.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have multiple effects in various tissues including adipose inflammation, a condition characterized by increased local release of the pro-lipolytic cytokine tumor necrosis factor-alpha (TNF-α). Whether miRNAs regulate adipocyte lipolysis is unknown. We set out to determine whether miRNAs affect adipocyte lipolysis in human fat cells. To this end, eleven miRNAs known to be present in human adipose tissue were over-expressed in human in vitro differentiated adipocytes followed by assessments of TNF-α and glycerol levels in conditioned media after 48 h. Three miRNAs (miR-145, -26a and let-7d) modulated both parameters in parallel. However, while miR-26a and let-7d decreased, miR-145 increased both glycerol release and TNF-α secretion. Further studies were focused therefore on miR-145 since this was the only stimulator of lipolysis and TNF-α secretion. Time-course analysis demonstrated that miR-145 over-expression up-regulated TNF-α expression/secretion followed by increased glycerol release. Increase in TNF-α production by miR-145 was mediated via activation of p65, a member of the NF-κB complex. In addition, miR-145 down-regulated the expression of the protease ADAM17, resulting in an increased fraction of membrane bound TNF-α, which is the more biologically active form of TNF-α. MiR-145 overexpression also increased the phosphorylation of activating serine residues in hormone sensitive lipase and decreased the mRNA expression of phosphodiesterase 3B, effects which are also observed upon TNF-α treatment in human adipocytes. We conclude that miR-145 regulates adipocyte lipolysis via multiple mechanisms involving increased production and processing of TNF-α in fat cells.
Lipid Laboratory, Department of Medicine (H7) Huddinge, Karolinska Institute, Stockholm, Sweden.
Silvia
S
Lorente-Cebrián
Lipid Laboratory, Department of Medicine (H7) Huddinge, Karolinska Institute, Stockholm, Sweden.
Niklas
N
Mejhert
Lipid Laboratory, Department of Medicine (H7) Huddinge, Karolinska Institute, Stockholm, Sweden.
Agné
A
Kulyté
Lipid Laboratory, Department of Medicine (H7) Huddinge, Karolinska Institute, Stockholm, Sweden.
Jurga
J
Laurencikiene
Lipid Laboratory, Department of Medicine (H7) Huddinge, Karolinska Institute, Stockholm, Sweden.
Gaby
G
Åström
Akademikliniken, Stockholm, Sweden.
Pér
P
Hedén
Lipid Laboratory, Department of Medicine (H7) Huddinge, Karolinska Institute, Stockholm, Sweden.
Mikael
M
Rydén
Lipid Laboratory, Department of Medicine (H7) Huddinge, Karolinska Institute, Stockholm, Sweden.
Peter
P
Arner
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D008066:Lipolysis / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005990:Glycerol; D035683:MicroRNAs; D002787:Sterol Esterase; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C541010:MIRN145 microRNA, human; C528163:MIRN26 microRNA, human; C487931:mirnlet7 microRNA, human; C000606462:ADAM17 protein, human