Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men

Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Copenhagen, Denmark. [email protected] BACKGROUND: Stimulation of energy expenditure (EE) with selective thermogenic beta-adrenergic agonists may be a promising approach for treating obesity. OBJECTIVE: We analyzed the effects of the highly selective human beta(3)-adrenergic agonist L-796568 on 24-h EE, substrate oxidation, and body composition in obese, weight-stable men. DESIGN: In this 2-center, double-blind, randomized, parallel-group study, we measured 24-h EE before and after 28 d of treatment with L-796568 (375 mg/d) or placebo during weight maintenance (ie, without dietary intervention) in nondiabetic, nonsmoking men aged 25-49 y with body mass index (in kg/m(2)) of 28-35 (n = 10 subjects per treatment group). RESULTS: The mean change in 24-h EE from before to after treatment did not differ significantly between groups (92 +/- 586 and 86 +/- 512 kJ/24 h for the L-796568 and placebo groups, respectively). The change in 24-h nonprotein respiratory quotient from before to after treatment did not differ significantly between groups (0.009 +/- 0.021 and 0.009 +/- 0.029, respectively). No changes in glucose tolerance were observed, but triacylglycerol concentrations decreased significantly with L-796568 treatment compared with placebo (-0.76 +/- 0.76 and 0.42 +/- 0.31 mmol/L, respectively; P < 0.002). Overall, treatment-related changes in body composition were not observed, but higher plasma L-796568 concentrations in the L-796568 group were associated with greater decreases in fat mass (r = -0.69, P < 0.03). CONCLUSIONS: Treatment with L-796568 for 28 d had no major lipolytic or thermogenic effect but it lowered triacylglycerol concentrations. This lack of chronic effect on energy balance is likely explained by insufficient recruitment of beta(3)-responsive tissues in humans, down-regulation of the beta(3)-adrenergic receptor-mediated effects with chronic dosing, or both. Publication Types: Clinical Trial Randomized Controlled Tria

Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men

Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men. van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, Saris WH. Nutrition and Toxicology Research Institute (NUTRIM), Department of Human Biology, Maastricht University, The Netherlands. [email protected] OBJECTIVE: Our objective was to investigate the thermogenic efficacy of single oral doses of the novel beta(3)-adrenergic receptor agonist L-796568 [(R )-N -[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]-phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]-benzenesulfonamide, dihydrochloride] in humans. METHODS: Twelve healthy overweight to obese men participated in this 2-center, 3-period, randomized, placebo-controlled, crossover trial. In each period subjects received 250 mg L-796568, 1000 mg L-796568, or placebo. Energy expenditure and respiratory quotient were determined by indirect calorimetry; blood samples were taken; and ear temperature, heart rate, and blood pressure were measured at baseline and during the 4-hour period after administration. RESULTS: Energy expenditure increased significantly after the 1000-mg dose (about 8%) and this was accompanied by an increase in plasma glycerol and free fatty acid concentrations. Systolic blood pressure also increased significantly. No changes in heart rate, diastolic blood pressure, ear temperature, plasma catecholamine, potassium, or leptin were found. CONCLUSIONS: Single-dose administration of 1000 mg of the novel beta(3)-adrenergic receptor agonist L-796568 increased lipolysis and energy expenditure in overweight men. This is the first study to show such an effect of beta(3)-adrenergic receptor agonists in humans without significant evidence for beta(2)-adrenergic receptor involvement

The effects of TPA023, a GABA(A)alpha(2,3) subtype-selective partial agonist, on essential tremor in comparison to alcohol

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