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Effect of a 28-d treatment with L-796568, a novel ß₃-adrenergic receptor agonist, on energy expenditure and body composition in obese men^1,2,3

¹ From the Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Copenhagen (TML, ST, and AA); the Nutrition and Toxicology Research Institute (NUTRIM), Department of Human Biology, Maastricht University, Maastricht, Netherlands (MAVB and WHMS); and Merck & Co, Rahway, NJ (KMG and PL).

Background: Stimulation of energy expenditure (EE) with selective thermogenic ß-adrenergic agonists may be a promising approach for treating obesity.

Objective: We analyzed the effects of the highly selective human ß₃-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/m²) 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 ß₃-responsive tissues in humans, down-regulation of the ß₃-adrenergic receptor–mediated effects with chronic dosing, or both.

Key Words: L-796568 • ß3-adrenergic receptor • ß3-adrenergic receptor agonist • ß3 agonist • selectivity • energy expenditure • lipolysis • respiratory quotient • indirect calorimetry • triacylglycerol • obesity • obese men

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