Abstract
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.
Highlights
Excess body weight is a well-established risk factor for life-threatening diseases, including cardiovascular disease, type 2 diabetes and many types of cancer.Further, it can complicate and exacerbate chronic conditions such as musculoskeletal disorders and respiratory diseases [1,2].Behavioural therapies aimed at reducing caloric intake and increasing physical activity are typically ineffective and patients find difficulty adhering to regimes or diets designed for weight loss [3]
We investigated the copper ionophore disulfiram as a potential antiobesity agent, which has well-characterised pharmacokinetics in mice and humans [22,23] and established tolerance in patients treated for chronic alcoholism [24,25,26]
Mice treated with disulfiram even maintained body weights lower than mice fed normal chow (Figure 1A,B), despite consuming equal kJ/g body weight throughout the feeding regime (Figure 1C)
Summary
Excess body weight is a well-established risk factor for life-threatening diseases, including cardiovascular disease, type 2 diabetes and many types of cancer (e.g., breast, ovarian and prostate). It can complicate and exacerbate chronic conditions such as musculoskeletal disorders (e.g., osteoarthritis) and respiratory diseases (e.g., chronic obstructive pulmonary disease) [1,2]. Wilson’s disease, a genetic disorder (ATP7B mutation) causing hepatic copper accumulation, have weight loss as a reported symptom [8,9,10,11]. Murine models of Wilson’s disease have elevated hepatic copper coupled with downregulated hepatic lipid metabolism and decreased body weight [12,13]. We sought to determine whether the FDA-approved copper ionophore disulfiram could moderate weight gain in mice
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