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Copper ionophores as novel antiobesity therapeutics

Meggyesy, Peter M., Masaldan, Shashank, Clatworthy, Sharnel A. S., Volitakis, Irene, Eyckens, Daniel J., Aston-Mourney, Kathryn and Cater, Michael A. 2020, Copper ionophores as novel antiobesity therapeutics, Molecules, vol. 25, no. 21, pp. 1-15, doi: 10.3390/molecules25214957.

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Title Copper ionophores as novel antiobesity therapeutics
Author(s) Meggyesy, Peter M.
Masaldan, Shashank
Clatworthy, Sharnel A. S.
Volitakis, Irene
Eyckens, Daniel J.
Aston-Mourney, KathrynORCID iD for Aston-Mourney, Kathryn orcid.org/0000-0003-1412-6715
Cater, Michael A.
Journal name Molecules
Volume number 25
Issue number 21
Article ID 4957
Start page 1
End page 15
Total pages 15
Publisher MDPI
Place of publication Basel, Switzerland
Publication date 2020-10
ISSN 1420-3049
1420-3049
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Physical Sciences
Biochemistry & Molecular Biology
Chemistry, Multidisciplinary
Chemistry
disulfiram
H-2(gtsm)
obesity
copper
ionophore
Antabuse
fat metabolism
DOSE-EFFECT RELATIONSHIP
FATTY LIVER-DISEASE
ALDEHYDE DEHYDROGENASE
DISULFIRAM TREATMENT
INSULIN-RESISTANCE
HUMAN VOLUNTEERS
SERUM COPPER
BODY-WEIGHT
MOUSE MODEL
H2(gtsm)
Summary 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.
Language eng
DOI 10.3390/molecules25214957
Indigenous content off
Field of Research 0304 Medicinal and Biomolecular Chemistry
0305 Organic Chemistry
0307 Theoretical and Computational Chemistry
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30145102

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.