Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men
Open accessAbstract
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.
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Attempts to find functional BAT or utilize its thermogenesis for weight loss in humans have been largely unsuccessful.
“Histological evidence has indicated that brown fat is present, albeit in small amounts, in adults, throughout life 76, but attempts to find functional BAT 77 or utilize its thermogenesis for weight loss 78,79 have been largely unsuccessful.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [79]
The effect of L-796568 seemed to be lost after 28 days of treatment.
“One β3 agonist, L-796568, increased lipolysis and energy expenditure in overweight men acutely 142, but its effect seemed to be lost after 28 days of treatment 79,141.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [79]
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- Authors
- Larsen, T. M., Toubro, S., van Baak, M. A., Gottesdiener, K. M., Larson, P., Saris, W. H., & Astrup, A.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Copenhagen (DK)
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 76
- Issue
- 4
- Pages
- 780-788
- ISSN
- 0002-9165 (ISSN-L)
- OpenAlex
- W2139904173
- Cited by
- 179
- References
- 46
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 13 · 2021: 11 · 2020: 7 · 2019: 7 · 2018: 9 · 2017: 5 · 2016: 14 · 2015: 15 · 2014: 9 · 2013: 6 · 2012: 6
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal of Clinical Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- beta3-adrenergic agonists, obesity, energy expenditure, body composition, fat mass, triglycerides, substrate oxidation, respiratory quotient, lipolysis, thermogenesis, receptor down-regulation, glucose tolerance, plasma drug concentration, weight maintenance, pharmacological weight loss, beta-adrenergic agonists
- MeSH terms
- Benzenesulfonamides, Adult, Blood Glucose, Body Composition, Calorimetry, Indirect, Cholesterol, Diet, Double-Blind Method, Energy Metabolism, Fasting, Fatty Acids, Glucose Tolerance Test, Humans, Insulin, Kinetics, Male, Middle Aged, Obesity, Placebos, Sulfonamides, Thiazoles, Triglycerides, Adrenergic beta-3 Receptor Agonists
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