Beta-3 Adrenergic Receptor Activation Increases Resting Energy Expenditure and Brown Adipose Tissue Activity in a Cool Environment

Abstract

Purpose: Brown adipose tissue (BAT) is highly thermogenic and contributes to non-shivering thermogenesis. Acute mirabegron (MIRA) ingestion, ranging in doses from 50-200 mg, stimulates beta-3-adrenergic receptors in BAT. This increases resting energy expenditure (REE) and elevates supraclavicular skin temperature (Tsc, marker of BAT activation) in thermoneutral environments for up to 4 h. However, it is not known if the thermogenic effects of different MIRA doses are also observed during exposure to a cool environment. We tested the hypotheses that EE and markers of BAT activity during a 6 h cool environmental exposure would be greater following each dose of MIRA (100 mg, 150 mg and 200 mg) versus a placebo (PLA). Methods: 11 healthy adults (age: 22±2 y; BMI: 26±4 kg/m2; 5 women) completed four, double-blind, randomized study visits involving the acute ingestion of 100 mg, 150 mg, and 200 mg of MIRA (Myrbetriq; Astellas Pharma US) or PLA. 30 min following ingestion, subjects rested in a semi-recumbent position for 6 h in a whole-body indirect calorimeter (20°C, 50% RH). REE was calculated for each study visit. O2 consumption (VO2; ml/kg/min), CO2 production (VCO2; ml/kg/min), and respiratory exchange ratio (RER) were averaged over the last 10 min of each 30 min block. BAT activity was estimated using Tsc assessed via infrared thermography every 30 min and expressed relative to sternal skin temperature and as the area under the curve (AUC) for relative Tsc for each study visit. Mean skin temperature (Tsk; 12 sites), and rectal temperature (Tc) were measured every 30 min. Thermal comfort (1=comfortable, 4=very uncomfortable) and sensation (1=cold, 7=hot) were measured every 30 min. Values are reported as mean ± SD. Results: REE during the 6 h intervention was greater following ingestion of 100 mg (494±75 kcal; p < 0.001), 150 mg (481±67 kcal; p = 0.017), and 200 mg (492±69 kcal; p = 0.001) of MIRA vs. PLA (456±67 kcal). However, there were no differences in REE between doses ( p > 0.05 for all comparisons). There was a main effect of drug dose for VO2 ( p = 0.010), which was greater following ingestion of 100 mg (3.88±0.19 ml/kg/min; p = 0.007) and 150 mg (3.82±0.22 ml/kg/min; p = 0.046) of MIRA vs. PLA (3.59±0.11 ml/kg/min). There was a main effect of drug dose for VCO2 ( p = 0.019), which was greater following ingestion of 100 mg of MIRA vs. PLA (3.03±0.10 vs. 2.84±0.05 ml/kg/min; p = 0.004). There were no dose x time interactions or main effects of dose ( p = 0.421) for RER or BAT activity indexed via relative Tsc ( p > 0.237). However, the AUC for Tsc was greater following ingestion of 100 mg (12.54±7.51°C x min; p = 0.011), 150 mg (10.01±6.05°C x min; p = 0.021), and 200 mg (9.17±5.95°C x min; p = 0.028) of MIRA vs. PLA (4.74±3.86°C x min). There was a main effect of drug dose for Tsk ( p = 0.040) but there was no dose x time interaction ( p = 0.608) and there was no main effect of dose ( p = 0.155) for Tc. There was a main effect of dose for thermal sensation ( p = 0.040), which was greater following ingestion of 100 mg (2.9±0.3; p = 0.011) of MIRA vs. PLA (2.4±0.4). There was no dose x time interaction ( p = 0.528) or main effect of dose ( p = 0.080) for thermal comfort. Conclusions: Our data indicate that acute doses of MIRA (100 mg, 150 mg and 200 mg) elicit greater REE and BAT activity vs. PLA during a 6 h of exposure to a cool environment. However, REE and BAT activity was not different between the MIRA doses. This suggests that beta-3 adrenergic receptor activation in BAT appears to be a physiologically effective method to enhance thermogenesis in cool environments. Funded by: Offce of Naval Research N00014-21-1-2276. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.