Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice.

OBJECTIVE: To investigate the effect of SR141716, a selective CB1 receptor antagonist, on energy expenditure and on glucose uptake in isolated soleus muscle of Lep(ob)/Lep(ob) mice. DESIGN: Female Lep(ob)/Lep(ob) mice (8-10 weeks old) were treated with SR141716 (10 mg/kg, i.p. once daily) or vehicle for 7 days. MEASUREMENTS: Oxygen consumption, daily food and water intake, body weight and glucose uptake in isolated soleus muscle. RESULTS: SR141716 (10 mg/kg, i.p. once daily) resulted in a significant reduction of daily food intake (P<0.01) and body weight (P<0.05) 5 days after daily treatment. Body weight continued to be lower for the rest of the treatment period (P<0.05). There was no significant difference in body weight between the pair-fed and vehicle-treated animals. A 7-day treatment with SR141716 (10 mg/kg, i.p. once daily) caused 37% increase in basal oxygen consumption compared to that of vehicle-treated (90 min mean; P<0.01), and a significant 68% increase in glucose uptake in isolated soleus muscle preparations. CONCLUSION: It is concluded that SR141716 has a direct effect on energy expenditure suggesting that the antiobesity effect of SR141716 is due to activation of thermogenesis in addition to the initial hypophagia. The increase in soleus muscle glucose uptake with SR141716 treatment may contribute to the improved glycaemia seen in the previous studies.

Chronic CNS administration of Agouti-related protein (Agrp) reduces energy expenditure.

OBJECTIVE: To investigate whether the Agouti-related protein (Agrp), the melanocortin receptor antagonist, alters oxygen consumption, as a measure of energy expenditure. DESIGN: A 7-day intracerebroventricular administration of Agrp (1 nmol/day) in rats. MEASUREMENTS: Oxygen consumption was determined in closed-circuit respirometers on days 1 and 8. BRL-35135, a beta3-adrenoreceptor agonist known to activate the brown adipose tissue (BAT) thermogenesis directly and increase core temperature, was administered i.p. (40 microg/kg) on day 9 to challenge functionally the BAT. RESULTS: Agrp treatment caused a 54% increase in daily food intake and a 12% increase in body weight. An 8% decrease in VO(2) measurements was observed following ICV Agrp treatment on day 1. A similar decrease (7%) was observed on day 8. BRL-35135 stimulated colonic temperature in control rats. However, in the rats that had previously been treated with Agrp this effect was significantly blunted. CONCLUSION: Chronic CNS administration of Agrp decreases oxygen consumption and decreases the capacity of BAT to expend energy. The obesity observed following CNS administration of Agrp is the result of decreased energy expenditure and increased food intake.

Thermogenic effects of sibutramine and its metabolites.

1. The thermogenic activity of the serotonin and noradrenaline reuptake inhibitor sibutramine (BTS 54524; Reductil) was investigated by measuring oxygen consumption (VO2) in rats treated with sibutramine or its two pharmacologically-active metabolites. 2. Sibutramine caused a dose-dependent rise in VO2, with a dose of 10 mg kg(-1) of sibutramine or its metabolites producing increases of up to 30% that were sustained for at least 6 h, and accompanied by significant increases (0.5-1.0 degrees C) in body temperature. 3. Based on the accumulation in vivo of radiolabelled 2-deoxy-[3H]-glucose, sibutramine had little or no effect on glucose utilization in most tissues, but caused an 18 fold increase in brown adipose tissue (BAT). 4. Combined high, non-selective doses (20 mg kg(-1)) of the beta-adrenoceptor antagonists, atenolol and ICI 118551, inhibited completely the VO2 response to sibutramine, but the response was unaffected by low, beta1-adrenoceptor-selective (atenolol) or beta2-adrenoceptor-selective (ICI 118551) doses (1 mg kg(-1)). 5. The ganglionic blocking agent, chlorisondamine (15 mg kg(-1)), inhibited completely the VO2 response to the metabolites of sibutramine, but had no effect on the thermogenic response to the beta3-adrenoceptor-selective agonist BRL 35135. 6. Similar thermogenic responses were produced by simultaneous injection of nisoxetine and fluoxetine at doses (30 mg kg(-1)) that had no effect on VO2 when injected individually. 7. It is concluded that stimulation of thermogenesis by sibutramine requires central reuptake inhibition of both serotonin and noradrenaline, resulting in increased efferent sympathetic activation of BAT thermogenesis via beta3-adrenoceptor, and that this contributes to the compound's activity as an anti-obesity agent.