Abstract
Rimonabant, a cannabinoid antagonist, had emerged as a promising drug in the fight against obesity. In animals, rimonabant had been shown to affect both appetite and energy expenditure. Further investigation was required to determine the direct metabolic effect of rimonabant in humans. Fourteen obese postmenopausal women with a mean body mass index (BMI) of 32. 5kg/m2 (SEM +-0. 44) were randomised to receive either 20mg rimonabant daily alongside an isocaloric diet (drug group) or a hypocaloric diet designed to result in matching weight loss to that in the drug group (diet group). The aim was to determine if, when energy intake was maintained at pre treatment levels, rimonabant induced weight loss through an effect on energy expenditure and to also determine the direct effects of rimonabant on body fat distribution and gene expression. As weight loss itself may alter metabolism, a control group undertaking a dietary intervention matched for the weight loss in the rimonabant group were investigated. In this trial it was demonstrated, for the first time in humans, that treatment with rimonabant, whilst daily energy intake was maintained at pre-treatment levels, still induced weight loss (2. 6+/-0. 5kg). In a matched group, who followed a dietary intervention to achieve the same weight loss (3. 1 +-1. 1 kg), there was a decrease in resting energy expenditure (REE) (p=0. 05) which was not found in the rimonabant group, suggesting that rimonabant may influence energy expenditure. A decrease in total body fat (p=0. 046) and subcutaneous abdominal fat (p=0. 028) was found in the diet group only. No significant differences in gene expression were found in muscle, however in adipose tissue there was a difference in expression of PPAR (Peroxisome Proliferator-activated Receptor) delta between the two groups (p=0. 006) with PPAR delta decreasing post treatment in the rimonabant treated group. The trial produced interesting results with regards to the effect of rimonabant on REE and reinforced that the endocannabinoid system is a good potential target in the treatment of obesity. As antagonism of central receptors has been found to cause depression, however, an alternative medication to rimonabant that only produces the beneficial peripheral effects on energy expenditure is required. Previous research has demonstrated that not all obese individuals display the expected metabolic risk factors and there is a distinction between the metabolically 'healthy' and 'unhealthy'. Factors that may influence metabolic risk, such as body fat distribution and variations in lipid metabolism, require further research in order that future treatments may be targeted effectively. Therefore a follow on study to the main rimonabant intervention was undertaken to gain a comprehensive understanding of the gender differences in energy expenditure, body fat distribution and lipid metabolism in 12 obese males (mean BMI 31. 40 +- 0. 34 kg/m2) and 12 obese postmenopausal females (mean BMI 32. 39 +- 0. 53 kg/m2). Results showed that absolute REE was significantly higher in males than females (p<0. 01), however, once expressed per kg fat free mass (FFM), females had the significantly higher REE (p=0. 01). Males had significantly higher levels of internal fat (p=0. 001) and visceral fat (p=0. 003) and significantly lower levels of total body fat (p=0. 002) and subcutaneous abdominal fat (p=0. 004) than females. In adipose tissue, a significantly greater expression of Lipoprotein Lipase (LPL) was identified in females than males (p=0. 01), but there were no further significant differences in gene expression in adipose or muscle tissue between the genders. As there are gender differences in metabolism in obesity, there may be gender specific responses to any newly developed anti-obesity medications and these differences need to be evaluated.