title: Differential effects of GLP-1 receptor agonist on foam cell formation in monocytes between non-obese and obese subjects.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Yamakage
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Masuda
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Terada
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Muranaka
authors.affiliation: Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimatsu
authors.affiliation: Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. Electronic address: nsatoh@kuhp.kyoto-u.ac.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Satoh-Asahara
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000209:etiology*; D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D000077270:Exenatide; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000502:physiology; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D009765:Obesity / Q000150:complications*; D010455:Peptides / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D008077:Lipoproteins, LDL; D010455:Peptides; D014688:Venoms; C099252:oxidized low density lipoprotein; D000077270:Exenatide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Autophagy; Foam cell formation; Glucagon-like peptide-1; Monocytes; Obesity