Adipose Tissue MicroRNAs as Regulators of CCL2 Production in Human Obesity
- Erik Arner1,2,
- Niklas Mejhert2,
- Agné Kulyté2,
- Piotr J. Balwierz3,
- Mikhail Pachkov3,
- Mireille Cormont4,5,
- Silvia Lorente-Cebrián2,
- Anna Ehrlund2,
- Jurga Laurencikiene2,
- Per Hedén6,
- Karin Dahlman-Wright7,
- Jean-François Tanti4,5,
- Yoshihide Hayashizaki1,
- Mikael Rydén2,
- Ingrid Dahlman2,
- Erik van Nimwegen3,
- Carsten O. Daub1⇓ and
- Peter Arner2⇓
- 1RIKEN Omics Science Center, RIKEN Yokohama Institute, Yokohama, Kanagawa, Japan
- 2Department of Medicine, Huddinge, Lipid Laboratory, Karolinska Institutet, Stockholm, Sweden
- 3Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland
- 4INSERM U895, Mediterranean Center of Molecular Medicine, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France
- 5Faculty of Medicine, University of Nice Sophia-Antipolis, Nice, France
- 6Akademikliniken, Stockholm, Sweden
- 7Department of Biosciences and Nutrition, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Corresponding authors: Peter Arner (experimental and clinical correspondence), , and Carsten O. Daub (computational correspondence), .
E.A. and N.M. contributed equally to this study.
In obesity, white adipose tissue (WAT) inflammation is linked to insulin resistance. Increased adipocyte chemokine (C-C motif) ligand 2 (CCL2) secretion may initiate adipose inflammation by attracting the migration of inflammatory cells into the tissue. Using an unbiased approach, we identified adipose microRNAs (miRNAs) that are dysregulated in human obesity and assessed their possible role in controlling CCL2 production. In subcutaneous WAT obtained from 56 subjects, 11 miRNAs were present in all subjects and downregulated in obesity. Of these, 10 affected adipocyte CCL2 secretion in vitro and for 2 miRNAs (miR-126 and miR-193b), regulatory circuits were defined. While miR-126 bound directly to the 3′-untranslated region of CCL2 mRNA, miR-193b regulated CCL2 production indirectly through a network of transcription factors, many of which have been identified in other inflammatory conditions. In addition, overexpression of miR-193b and miR-126 in a human monocyte/macrophage cell line attenuated CCL2 production. The levels of the two miRNAs in subcutaneous WAT were significantly associated with CCL2 secretion (miR-193b) and expression of integrin, α-X, an inflammatory macrophage marker (miR-193b and miR-126). Taken together, our data suggest that miRNAs may be important regulators of adipose inflammation through their effects on CCL2 release from human adipocytes and macrophages.
- Received October 27, 2011.
- Accepted March 9, 2012.
- © 2012 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.