The utility of animal models to evaluate novel anti‐obesity agents

Abstract

The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2011.164.issue-4 Abbreviations 5-HT, 5-hydroxytryptamine; CTA, conditioned taste aversion; DIO, dietary-induced obese; EMEA, European Medicines Agency; FDA, Food and Drug Administration; GLP, glucagon-like-peptide; MCH, melanin-concentrating hormone IntroductionAmong healthcare experts around the world, there is agreement that the global epidemic of obesity will be one of the leading causes of morbidity and mortality for current and future generations, unless the rise in the prevalence of this disorder is reversed. Indeed, the metabolic consequences of obesity are drivers of other life-threatening disorders including dyslipidaemia, hypertension, atherogenesis and Type 2 diabetes (for review see Heal et al., 2009). Once considered to be a problem mainly in Western cultures, developing nations have now joined the ranks of countries burdened by obesity. Indeed, a recent report from the World Health Organisation estimated that in 2008 approximately 500 million adults were obese and 1.5 billion were overweight worldwide (World Health Organisation, 2011).In terms of pharmacotherapy for obesity, only four new drugs have been registered for the treatment of obesity over the last 15 years: dexfenfluramine (Redux), sibutramine (Meridia, Reductil), orlistat (Xenical) and rimonabant (Acomplia). Furthermore, due to the incidence of side effects, orlistat (Europe; USA) remains, at the time of writing, the only marketed drug, with sibutramine having recently been withdra...

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