title: Compound C inhibits macrophage chemotaxis through an AMPK-independent mechanism.
abstract: 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.
authors.affiliation: College of Pharmacy, Woosuk University, Wanju, Jeonbuk 55338, Republic of Korea; Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea.
authors.forename: Youngyi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea. Electronic address: bhpark@jbnu.ac.kr.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Woosuk University, Wanju, Jeonbuk 55338, Republic of Korea. Electronic address: ejbae@woosuk.ac.kr.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Bae
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Chemotaxis; Compound C; Glucose uptake; Inflammation; Macrophage