Additive effects of miRNAs and transcription factors on CCL2 production in human white adipose tissue

  1. Peter Arner1
  1. 1Department of Medicine, Huddinge, Lipid Laboratory, Karolinska Institutet, Stockholm, Sweden
  2. 2RIKEN Center for Life Science Technologies, Division of Genomic Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan
  3. 3Department of Biosciences and Nutrition, Huddinge, Karolinska Institutet, Stockholm, Sweden
  4. 4Akademikliniken, Stockholm, Sweden
  1. Corresponding authors: Peter Arner, E-mail: peter.arner{at} Agné Kulyté, E-mail: agne.kulyte{at}


Adipose tissue inflammation is present in insulin resistant conditions. We recently proposed a network of microRNAs (miRNAs) and transcription factors (TFs) regulating the production of the pro-inflammatory chemokine (C-C motif) ligand-2 (CCL2) in adipose tissue. We presently extended and further validated this network and investigated if the circuits controlling CCL2 can interact in human adipocytes and macrophages. The updated sub-network predicted that miR-126/-193b/-92a control CCL2 production via several TFs, including ETS1, MAX and SP1. This was confirmed in human adipocytes by the observation that gene silencing of ETS1, MAX or SP1 attenuated CCL2 production. Combined gene silencing of ETS1 and MAX resulted in an additive reduction in CCL2 production. Moreover, overexpression of miR-126/-193b/-92a in different pair-wise combinations reduced CCL2 secretion more efficiently than either miRNA alone. However, while effects on CCL2 secretion by co-overexpression of miR-92a/-193b and miR-92a/-126 were additive in adipocytes, the combination of miR-126/-193b was primarily additive in macrophages. For miR-92a and -193b, their signals converged on the NFκB pathway. In conclusion, TF and miRNA-mediated regulation of CCL2 production is additive and partly relayed via cell-specific networks in human adipose tissue which may be important for the development of insulin resistance/type 2 diabetes.

  • Received May 3, 2013.
  • Accepted December 15, 2013.

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