Copper ionophores as novel antiobesity therapeutics
journal contributionposted on 01.10.2020, 00:00 authored by P M Meggyesy, S Masaldan, S A S Clatworthy, I Volitakis, D J Eyckens, Kathryn Aston-MourneyKathryn Aston-Mourney, M A Cater
The therapeutic utility of the copper ionophore disulfiram was investigated in a diet-induced obesity mouse model (C57BL/6J background), both through administration in feed (0.05 to 1% (w/w)) and via oral gavage (150 mg/kg) for up to eight weeks. Mice were monitored for body weight, fat deposition (perigonadal fat pads), metabolic changes (e.g., glucose dyshomeostasis) and pathologies (e.g., hepatic steatosis, hyperglycaemia and hypertriglyceridemia) associated with a high-fat diet. Metal-related pharmacological effects across major organs and serums were investigated using inductively coupled plasma mass spectrometry (ICP-MS). Disulfiram treatments (all modes) augmented hepatic copper in mice, markedly moderated body weight and abolished the deleterious systemic changes associated with a high-fat diet. Likewise, another chemically distinct copper ionophore H2(gtsm), administered daily (oral gavage), also augmented hepatic copper and moderated mouse body weight. Postmortem histological examinations of the liver and other major organs, together with serum aminotransferases, supported the reported therapeutic safety of disulfiram. Disulfiram specifically altered systemic copper in mice and altered hepatic copper metabolism, perturbing the incorporation of copper into ceruloplasmin (holo-ceruloplasmin biosynthesis) and subsequently reducing serum copper concentrations. Serum ceruloplasmin represents a biomarker for disulfiram activity. Our results establish copper ionophores as a potential class of antiobesity agents.
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Publication classificationC1 Refereed article in a scholarly journal
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Science & TechnologyLife Sciences & BiomedicinePhysical SciencesBiochemistry & Molecular BiologyChemistry, MultidisciplinaryChemistrydisulfiramH-2(gtsm)obesitycopperionophoreAntabusefat metabolismDOSE-EFFECT RELATIONSHIPFATTY LIVER-DISEASEALDEHYDE DEHYDROGENASEDISULFIRAM TREATMENTINSULIN-RESISTANCEHUMAN VOLUNTEERSSERUM COPPERBODY-WEIGHTMOUSE MODELH2(gtsm)