Rising levels of obesity and associated health problems in many countries worldwide have led to a burgeoning interest in drugs that could promote weight loss. Writing in the British Journal of Pharmacology, Pauwels and colleagues now provide evidence that a novel 5-hydroxytryptamine (5-HT)6 receptor partial agonist — known as E-6837 — could represent a novel approach for the management of obesity.

Several previous investigations have indicated that the 5-HT6 receptor, which is distributed almost exclusively within the central nervous system, could have potential as an anti-obesity target. However, there have until now been no studies published that have assessed the chronic effects of 5-HT6 receptor ligands on body weight in an animal model considered to closely mimic human obesity. So Pauwels et al. chose to evaluate the effects of chronic treatment with E-6837 in mature rats that had been given access to a highly palatable high-calorie diet, which develop obesity with insulin resistance and other metabolic disturbances.

During the 4-week treatment period, diet-induced obese (DIO) rats treated with E-6837 showed sustained weight loss and decreased food intake. Importantly, the weight loss was mediated exclusively by a ∼30% decrease in fat mass, with no losses in protein or water, and the decrease in adiposity resulted in a significant improvement in glycaemic control. The rats were also studied for a 6-week period after treatment, and their weights were still significantly lower than those of vehicle-treated control rats at the end of this period, indicating that weight is not rapidly regained following treatment cessation.

The authors also assessed the effects of sibutramine, one of the few anti-obesity drugs approved so far, in DIO rats as a positive control. The onset of the weight-loss effect of E-6837 was slower than that of sibutramine, but the maximal effect was greater. Furthermore, although some weight regain occurred after treatment cessation with both E-6837 and sibutramine, the body weights after E-6837 remained lower.

At present, the mechanisms by which modulation of the 5-HT6 receptor by E-6837 affects food intake are not clear. Nevertheless, the results of Pauwels et al. suggest that such ligands have promise as a CNS-mediated strategy for combating obesity, with the potential to result in greater sustained weight loss than sibutramine.