Adipose Tissue MicroRNAs as Regulators of CCL2 Production in Human Obesity

Erik Arner; Niklas Mejhert; Agné Kulyté; Piotr J. Balwierz; Mikhail Pachkov; Mireille Cormont; Silvia Lorente-Cebrián; Anna Ehrlund; Jurga Laurencikiene; Per Hedén; Karin Dahlman-Wright; Jean-François Tanti; Yoshihide Hayashizaki; Mikael Rydén; Ingrid Dahlman; Erik van Nimwegen; Carsten O. Daub; Peter Arner


Diabetes. 2012;61(8):1986-1993. 

In This Article

Abstract and Introduction


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.


Obesity is associated with a low-grade inflammatory state in white adipose tissue (WAT), which influences fat cell function and may promote insulin resistance and type 2 diabetes.[1,2] Adipocytes and infiltrating inflammatory cells (primarily macrophages) present within the tissue secrete key inflammatory proteins, such as tumor necrosis factor-α, interleukin (IL)-6, and chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein, and their gene expression and release are markedly increased in obesity.[3,4] CCL2 may be particularly important since it has been proposed to initiate adipose inflammation by attracting inflammatory cells from the blood stream into WAT.[5,6] Studies in mice show that CCL2 production and signaling are essential for the development of WAT inflammation.[7] Although a number of different cell types in WAT may produce CCL2, the fat cells are of particular interest since adipocyte-derived CCL2 may promote local inflammation independent of the presence of macrophages/leukocytes in human WAT.[8] However, the mechanisms controlling WAT CCL2 production in obesity are not clear.

The pathogenesis of obesity involves a complex interplay between various types of factors. At the molecular level, such interdependencies can be conceptualized as transcriptional regulatory networks with regulatory proteins and different classes of RNA molecules as nodes and their interactions as edges.[9] Gene transcription is controlled at several different levels of which some have been elucidated only in recent years. MicroRNAs (miRNAs) have emerged as important factors regulating gene expression through binding to complementary sequences of target mRNAs resulting in decreased mRNA levels.[10] Alterations in the levels of miRNAs have been shown to affect gene expression and thereby cell function in several pathophysiological conditions, including inflammation.[11] The miRNAs may act directly on the target genes or indirectly by first regulating transcription factors (TFs), which, in turn, control the expression of genes.[11] The role of miRNAs in adipose inflammation and obesity is, however, not known.

In this study, we aimed to define adipose miRNAs dysregulated in human obesity and their possible role in controlling CCL2 production. Through a systematic and unbiased approach, we were able to identify 10 obesity-regulated miRNAs that affected adipocyte CCL2 secretion in vitro. For two of these (miR-126 and miR-193b), we could define their mechanism of action, which involved direct or indirect (through TFs) regulation of CCL2 production in human adipocytes and macrophages.


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