Differential effects of GLP-1 receptor agonist on foam cell formation in monocytes between non-obese and obese subjects

• Published in: Metabolism, clinical and experimental Vol. 65; no. 2; pp. 1 - 11
• Main Authors: Tanaka, Masashi, Matsuo, Yoshiyuki, Yamakage, Hajime, Masuda, Shinya, Terada, Yuko, Muranaka, Kazuya, Wada, Hiromichi, Hasegawa, Koji, Shimatsu, Akira, Satoh-Asahara, Noriko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2016
• Subjects: Adult; Atherosclerosis - etiology; Autophagy; Autophagy - drug effects; Cells, Cultured; Endocrinology & Metabolism; Female; Foam cell formation; Foam Cells - drug effects; Foam Cells - physiology; Glucagon-like peptide-1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - physiology; Humans; Lipoproteins, LDL - pharmacology; Male; Middle Aged; Monocytes; Monocytes - drug effects; Monocytes - physiology; Obesity; Obesity - complications; Peptides - pharmacology; Venoms - pharmacology; Obesity; GLP-1; PKA; DPP-4; Mϕ; AGEs; Autophagy; Ox-LDL; NF-κB; Monocytes; Glucagon-like peptide-1; Foam cell formation; Ex-4; TLR; LC3; GLP-1R; oxidized-LDL; GLP-1 receptor; glucagon-like peptide-1; advanced glycation end products; microtubule-associated protein 1 light chain 3; macrophages; dipeptidyl peptidase-4; muclear factor-κB; protein kinase A; exendin-4; Toll-like receptor
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2015.10.009

Monocytes/macrophages (Mϕ) transform into foam cells in the presence of oxidized-LDL (ox-LDL), releasing inflammatory mediators. The antiatherogenic role of a dipeptidyl peptidase-4 inhibitor is mediated, in part, through improving the unbalance of inflammatory (M1)/anti-inflammatory (M2) phenotypes in monocytes. In this study, we examined differential regulation of glucagon-like peptide-1 receptor (GLP-1R) signaling for antiatherogenesis in monocytes/Mϕ from normal-weight control subjects and obese patients. We evaluated the effects of exendin-4 (Ex-4), a GLP-1R agonist, on ox-LDL-stimulated foam cell formation, M1/M2 cytokine production, and organelle change in primary monocytes from control subjects and obese patients and human monocytic THP-1-derived Mϕ as well. Here we report that Ex-4 suppressed foam cell formation and M1 cytokine expression and, interestingly, induced indicators of autophagy in ox-LDL-stimulated monocytes from control subjects. The suppressing effects on foam cell formation by Ex-4 were reversed by a cAMP inhibitor. In contrast to control subjects, Ex-4 did not induce indicators of autophagy, but did induce foam cell formation and M1 cytokine expression in monocytes from obese patients. GLP-1R expression level was comparable between control subjects and obese patients. The effects of Ex-4 on inducing indicators of autophagy and suppressing foam cell formation were observed in THP-1 Mϕ. These data suggest that GLP-1R signaling induces autophagy, thereby suppressing foam cell formation in non-obese subjects. In obese patients, GLP-1R stimulation increased foam cell formation and IL-6, TNF-α, and IL-1β production. Such altered signaling in monocytes of obese patients may be involved in the development of atherosclerosis.