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.