Beta Adrenergic Mediated Thermogenesis: Non-selective Stimulation With And Without Beta-3 Agonism In Men And Women

Intravenous delivery of the non-selective beta-adrenergic receptor (βAR) agonist, isoproterenol, evokes a thermogenic response in adult humans. Ingestion of the β3AR agonist, mirabegron, also stimulates thermogenesis, a response that has been attributed to activation of brown adipose tissue. Recently, controversy has arisen as to the βAR subtype chiefly responsible for brown adipose thermogenesis. In addition, although sex has been shown to influence mirabegron pharmacokinetics, sex differences in the thermogenic response are unclear. PURPOSE: To compare the magnitude of increase in whole-body thermogenesis and brown adipose activation during incremental, non-specific βAR stimulation, with and without β3AR agonism, in adult men and women. METHODS: 19 healthy, active young adults (9 males, 10 females) participated in a randomized crossover study. Energy expenditure in a temperature-controlled room (22.1 °C, 41.9% relative humidity) was determined at rest and after ingestion of placebo or mirabegron (100 mg), prior to intravenous delivery of isoproterenol (30 minutes at 6, 12, and 24 ng/kg fat free mass (FFM)/min). Brown adipose activity was estimated using supraclavicular skin temperature assessed via infrared thermography. RESULTS: Isoproterenol increased energy expenditure above rest to a greater extent (P = 0.02) in women (12 ± 11, 17 ± 10, 22 ± 14% (mean ± SD)) compared with men (4 ± 4, 6 ± 6, 13 ± 9%); mirabegron augmented this response in both sexes (P < 0.001), but by a greater (P = 0.03) magnitude in women (19 ± 8, 29 ± 17, 27 ± 13%) compared with men (11 ± 7, 15 ± 7, 20 ± 8%). Supraclavicular skin temperature was increased with 12 and 24 ng/kg FFM/min of isoproterenol (0.27 ± 0.08, 0.35 ± 0.08 °C); these increases were unaffected by either mirabegron (P = 0.91) or sex (P = 0.21). CONCLUSION: Targeted β3AR stimulation augments the thermogenic response to non-selective βAR stimulation in a manner independent of brown adipose activation. These preliminary data imply that β3ARs might not be the primary regulator of brown adipose activation in humans and/or there is an upper limit to the contribution of brown adipose activation to whole body thermogenesis. Finally, females appear to have a greater thermogenic response to non-selective βAR stimulation. Office of Naval Research N00014-21-1-2276