Abstract
Background
The metabolic syndrome is defined by the presence of obesity, insulin resistance, dyslipidemia, and hypertension. Advanced glycation end products (AGEs) are stable end products of the Maillard reaction, whereby AGE accumulation is considered not only a biomarker of aging but is also associated with several degenerative diseases. AGEs are recognized by several receptor molecules of which the receptor of AGEs (RAGE) is currently the most intensively studied receptor. Activation of RAGE causes an unfavorable proinflammatory state and deletion of RAGE in diabetic animals has been reported to protect against atherosclerosis. AGEs and a high fat diet are associated with cardiovascular diseases, whereas is still not clear whether a direct link between high fat nutrition and AGEs exists in vivo.
Materials and methods
C57BL/6 and C57BL/6 RAGE −/− mice were fed a high fat diet to induce obesity. Weight, insulin, lipid levels, AGE modifications, and cardiac gene expression were analyzed.
Results
The absence of RAGE resulted in accelerated weight gain, increased plasma cholesterol, and higher insulin levels in obese mice. The hearts of normal and obese RAGE −/− mice contained lower levels of the AGE arginine–pyrimidine and 3DG-imidazolone than RAGE + / + animals. RAGE −/− mice also exhibited lower expression of the genes encoding the antioxidative enzymes MnSOD, Cu/ZnSOD, and ceruloplasmin in cardiac tissue, whereas the AGE receptors AGER-1, -2, and -3 were equally expressed in both genotypes. Obese mice of both strains expressed increased amounts of AGER-2. Only obese RAGE + / + mice exhibited a reduced mRNA accumulation of Cu/Zn SOD.
Conclusion
These data suggest that RAGE is involved in the development of obesity and insulin resistance.
Zusammenfassung
Hintergrund
Das metabolische Syndrom ist durch Übergewicht, Insulinresistenz, Dyslipämie und Bluthochdruck charakterisiert. Die „advanced glycation end products“ (Glykierungsendprodukte, AGEs) sind Endprodukte der Maillard-Reaktion, deren Akkumulation als Biomarker des Alterns gilt und mit degenerativen Erkrankungen assoziiert ist. Die AGEs werden von spezifischen Bindemolekülen erkannt, von denen RAGE derzeit der meistuntersuchte Rezeptor ist. Die RAGE-Aktivierung verursacht einen unerwünschten proinflammatorischen Zustand und diabetische Mäuse ohne RAGE sind offenbar gegen Artherosklerose geschützt. Sowohl AGEs als auch Hochfettdiät sind mit kardiovaskulären Erkrankungen verknüpft, aber es ist nicht klar, ob eine direkte Verbindung zwischen fettreicher Ernährung und AGE-Akkumulation existiert.
Material und Methoden
Mäuse mit und ohne das RAGE-Gen wurden mit einer fettreichen Diät gefüttert. Gewicht, Plasmainsulin und -Lipidgehalte sowie AGE-Modifikationen und Genexpression im Herzen wurden bestimmt.
Ergebnisse
Das Fehlen von RAGE verursachte eine schnellere Gewichtszunahme und in adipösen Tieren erhöhte Plasmainsulin- und -Cholesterinwerte. Die Herzen normalgewichtiger und adipöser RAGE-Knock-out-Mäuse enthielten geringere Mengen der AGEs Argininpyrimidin und 3-DG-Imidazolon als die Herzen der Tiere mit RAGE (+/+). Die Expression der Gene für die AGE-Rezeptoren AGER-1, -2 und -3 war in den Herzen beider Mausstämme vergleichbar, wohingegen die Gene für die antioxidativ wirkenden Enzyme MnSOD, Cu/ZnSOD und Ceruloplasmin in RAGE-K.-o.-Mäusen geringer exprimiert waren. Bei den adipösen Tieren zeigten nur die RAGE + / +- Mäuse eine reduzierte Akkumulation der Cu/ZnSOD im Vergleich zur Kontrollgruppe. AGER-2 wurde hingegen in adipösen Tieren beider Stämme verstärkt exprimiert.
Schlussfolgerung
Die Ergebnisse lassen vermuten, dass RAGE die Entwicklung von Adipositas und Insulinresistenz beeinflusst.
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Acknowledgments
The authors wish to thank Prof. Nawroth and Prof. Arnold (DKFZ, Heidelberg, Germany) for the opportunity to use the RAGE −/− mouse strain for this work. Excellent technical assistance by Thekla Wangemann is gratefully acknowledged. This work was funded by a DFG-grant to A.S. (DFG, Si-1317/1–1) and B.L. by the “Freunde und Förderer der Martin-Luther-Universität Halle-Wittenberg,” the “Stiftungsfond Dresdner Bank im Stifterverband für die Deutsche Wissenschaft” and the “Stadt- und Kreissparkasse Halle.”
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The corresponding author states that there are no conflicts of interest.
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Leuner, B., Max, M., Thamm, K. et al. RAGE influences obesity in mice. Z Gerontol Geriat 45, 102–108 (2012). https://doi.org/10.1007/s00391-011-0279-x
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DOI: https://doi.org/10.1007/s00391-011-0279-x