Compound C inhibits macrophage chemotaxis through an AMPK-independent mechanism

• Published in: Biochemical and biophysical research communications Vol. 469; no. 15; pp. 515 - 520
• Main Authors: Lee, Youngyi, Byung-Hyun Park, Eun Ju Bae
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 2016
• Subjects: adipocytes; adipose tissue; AMP-activated protein kinase; AMPK; anti-inflammatory activity; cell movement; chemoattractants; chemokine CCL2; chemotaxis; Compound C; FAK; genes; Glucose uptake; inducible nitric oxide synthase; inflammation; insulin resistance; lipopolysaccharides; Macrophage; macrophages; NF-κB; non-specific protein-tyrosine kinase; transcription factor NF-kappa B; tumor necrosis factor-alpha
• ISSN: 0006-291X; 1090-2104

Macrophage infiltration in adipose tissue is a well-established cause of obesity-linked insulin resistance. AMP-activated protein kinase (AMPK) activation in peripheral tissues such as adipose tissue has beneficial effects on the protection against obesity-induced insulin resistance, which is mainly mediated by prevention of adipose tissue macrophage infiltration and inflammation. In examining the role of AMPK on adipose tissue inflammation, we unexpectedly found that compound C (CC), despite its inhibition of AMPK, robustly inhibited macrophage chemotaxis in RAW 264.7 cells when adipocyte conditioned medium (CM) was used as a chemoattractant. Here, we report that CC inhibition of macrophage migration occurred independently of AMPK. Mechanistically, this inhibitory effect of cell migration by CC was mediated by inhibition of the focal adhesion kinase, AKT, nuclear factor κB pathways. Moreover, the expression of chemokine monocyte chemoattractant protein-1 and pro-inflammatory genes such as tumor necrosis factor α and inducible nitric oxide synthase were prevented by CC treatment in RAW 264.7 cells stimulated with either adipocyte CM or lipopolysaccharide. Lastly, in accord with the findings of the anti-inflammatory effect of CC, we demonstrated that CC functioned as a repressor of macrophage CM-mediated insulin resistance in adipocytes. Taken together, our results suggest that CC serves as a useful inhibitory molecule against macrophage chemotaxis into adipose tissue and thus might have therapeutic potential for the treatment of obesity-linked adipose inflammation.