Abstract
In this thesis the effects of rimonabant, the CB1 endocannabinoid receptor antagonist, and gender on free fatty acid (FFA) and very-low-density lipoprotein (VLDL)-triacylglycerol kinetics, insulin sensitivity and circulating adipokines was examined in obese postmenopausal women and age- and body mass index (BMI)- matched men. In the first study, the effect of rimonabant (20 mg/day for 12 weeks, with energy intake matched for energy requirements) was compared with the effect of a hypocaloric diet (to achieve the same weight loss as on the rimonabant treatment, for 12 weeks). Fourteen obese (BMI=33.0±0.5 kg/m2), postmenopausal, aged 57.8±4.7 years Caucasian women were randomised to the 2 treatments and the following was measured at the baseline and after 12 weeks: FFA kinetics, VLDL-triglyceride kinetics; insulin sensitivity; circulating fasting glucose, FFA, glycerol, triglycerides, VLDL1 and VLDL2-triglycerides, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, leptin, adiponectin and insulin. In the second study, the same variables were compared between 16 obese postmenopausal Caucasian women (57.9±5.4 years, BMI=32.8±1.8 kg/m 2) and 7 age- and BMI- matched men (60.6±6.6 years, BMI=31.5±1.4 kg/m2). Results: Weight loss was not different between 2 treatment groups in the first study (2.6±1.4 kg in the rimonabant group vs. 3.1±2.8 kg in the diet group, p > 0.05). Rimonabant treatment increased palmitate rates of appearance (Ra), metabolic clearance rates (MCR) and oxidation rates, while dietary treatment did not influence these variables. The effect of rimonabant on palmitate oxidation rates was significantly different from the effect of the hypocaloric diet, as well as the effect on VLDL1 and VLDL2-triglyceride absolute production rates (APR), circulating fasting triglycerides, VLDL1- and VLDL2-triglycerides, glucose, insulin and homeostasis model assessment (HOMA)-estimates of insulin sensitivity. Both treatments similarly increased adiponectin and decreased leptin. Neither treatment significantly changed insulin sensitivity estimated by hyperinsulinaemic-euglycaemic clamp. In the second study, women had higher palmitate Ra, MCR, non-oxidative disposal and total plasma fatty acid oxidation (TPFAO) rates, VLDL1 and VLDL2-triglyceride fractional clearance rates (FCR), circulating leptin, glycerol and FFA. The other variables were not significantly different. In conclusion, the increase in fatty acid turnover and oxidation may be the mechanism by which the weight loss was achieved by rimonabant treatment, without caloric restriction. The effects of rimonabant on FFA and VLDL-kinetics, insulin sensitivity and metabolic parameters, were the opposite from the effects of the hypocaloric diet, although the weight loss was similar. Postmenopausal obese women, compared with age- and BMI-matched men, have higher rates of fatty acid turnover, accounted by both increased metabolic clearance, non-oxidative disposal and increased fatty acid oxidation. However, their metabolic profile was not different from the men. This suggests that women are intrinsically “primed” for increased lipid turnover, without a significant deterioration of metabolic risk.