Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans.
Abstract
Stimulation of beta3-adrenoceptors by selective agonists improves insulin action and stimulates energy metabolism in various rodent models of obesity and type 2 diabetes. Whether selective beta3-adrenoceptor stimulation exerts metabolic actions in humans remains to be proven. The effects of a highly selective beta3-adrenoceptor agonist on insulin action, energy metabolism, and body composition were assessed in 14 healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat [mean +/- SD]) randomly assigned to 8 weeks of treatment with either 1,500 mg/day of CL 316,243 (n = 10) or placebo (n = 4). Insulin-mediated glucose disposal (IMGD), nonoxidative glucose disposal (NOGD), oxidative glucose disposal (OGD) (indirect calorimetry), and splanchnic glucose output (SGO; beta3-[H3]glucose) were determined during a 100-min hyperinsulinemic-euglycemic glucose clamp (40 mU x m(-2) x min(-1)) before and after 4 and 8 weeks of treatment. The 24-h energy expenditure (24-EE), 24-h respiratory quotient (24-RQ), and the oxidation rates of fat and carbohydrate were determined in a respiratory chamber before and after 8 weeks. After 4 weeks, treatment with CL 316,243 increased IMGD (+45%, P < 0.01) in a plasma concentration-dependent manner (r = 0.76, P < 0.02). This effect was due to an 82% increase in NOGD (P < 0.01), while OGD and SGO remained unchanged. The effects on insulin action were markedly diminished after 8 weeks; this was significantly related to an unexpected decline in the plasma concentrations of CL 316,243 (-36%, P = 0.08). At this time, 24-RQ was lowered (P < 0.001), corresponding to a 23% increase in fat oxidation (P < 0.01) and a 17% decrease in carbohydrate oxidation (P = 0.05). The 24-EE after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Plasma concentrations of glucose, insulin, and leptin were unaffected by treatment, while free fatty acid concentrations increased by 41% (P < 0.05), again linearly with the achieved plasma concentration of CL 316,243 (r = 0.67, P < 0.05). Treatment with CL 316,243 had no effect on heart rate or blood pressure and caused no cases of tremors. We conclude that treatment of lean male subjects with CL 316,243 increases insulin action and fat oxidation, both in a plasma concentration-dependent manner. This is the first study to demonstrate unequivocal metabolic effects of a highly selective beta3-adrenoceptor agonist in humans.
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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 [78]
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- Authors
- Weyer, C., Tataranni, P. A., Snitker, S., Danforth, E., & Ravussin, E.
- Affiliations
- National Institutes of Health (US)
- Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA. cweyer@phx.niddk.nih.gov
- ORCID
- Snitker, S
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1998-10-01
- Volume
- 47
- Issue
- 10
- Pages
- 1555-1561
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2090592868
- Cited by
- 188
- References
- 13
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 12 · 2015: 12 · 2014: 6 · 2013: 4 · 2012: 5
- FWCI
- 7.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- CL316,243, beta3-adrenergic agonists, insulin action, insulin-stimulated glucose disposal, nonoxidative glucose disposal, fat oxidation, carbohydrate oxidation, respiratory quotient, energy expenditure, body composition, plasma drug concentration, type 2 diabetes, obesity, energy metabolism
- MeSH terms
- Adrenergic beta-Agonists, Adult, Blood Glucose, Body Composition, Body Weight, Dioxoles, Double-Blind Method, Energy Metabolism, Fatty Acids, Nonesterified, Humans, Insulin, Male, Oxidation-Reduction, Proteins, Glucose Clamp Technique, Leptin, Lipid Metabolism
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