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USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events.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.

Figure 1

The effect of phentermine and topiramate alone and in combination on body weight in rats with dietary-induced obesity. Female Wistar rats were maintained on reverse-phase lighting (lights out 09.30–17.30 h) with free access to powdered high-fat chow, chocolate, peanuts and tap water during the induction of obesity (14 weeks) and throughout the feeding study. After a 7 day run-in period, during which rats were dosed orally with vehicle once daily, rats were dosed orally with vehicle, topiramate, phentermine or topiramate plus phentermine once daily for 41 days. Topiramate was given in a dose of 30 mg·kg⁻¹ (increased to 60 mg·kg⁻¹ on Day 15). Phentermine was given in a dose of 5 mg·kg⁻¹. Rats, feeding jars and water bottles were weighed every day at the time of dosing, which was at the onset of the dark period. Topiramate and phentermine were dissolved in 1% Tylose MH50/0.1% poloxymer (in deionized water; dose volume 1 mL·kg⁻¹). All doses are for the free base. Results are adjusted means ± SEM; n = 10. *P < 0.05 (vs. controls), †P < 0.05 (topiramate plus phentermine vs. topiramate alone), ‡P < 0.05 (topiramate plus phentermine vs. both topiramate and phentermine alone). Numbers represent % reduction in body weight compared with the control group on Day 42.

Figure 2

The effect of phentermine and topiramate alone and in combination on food intake in rats with dietary-induced obesity. Food intake data are expressed as kJ·kg⁻¹ to take account of the different caloric values of the diet components (high fat chow, peanuts and chocolate). Results are adjusted means ± SEM; n = 9–10. *P < 0.05 (vs. controls), ‡P < 0.05 (topiramate plus phentermine vs. both topiramate and phentermine alone).

Figure 3

A comparison of the weight-loss produced by various anti-obesity drugs in man versus the body weight loss over a 28 day dosing period observed in the DIO rat. Correlation r²= 0.82. Figure adapted from Heal et al., 2011. DIO rat data taken from Jackson et al., 2004, Jackson et al., 2005, Jackson et al., 2007. Human data taken from Bray et al., 2003, http://www.vivus.com/pipeline/qnexa-obesity, Pi-Sunyer et al., 2006, Després et al., 2005, Apfelbaum et al., 1999, Hauptman et al., 2000, James et al., 2000.