Pharmacological Activation of Brown Adipose Tissue Enhances Cold Resiliency during Progressive Cold-Water Immersion

Background: Acute mirabegron (MIRA) ingestion, a pharmaceutical that activates β3-adrenergic receptors on brown adipose tissue (BAT), enhances energy expenditure during thermoneutral and cool air exposure (i.e., 20°C). Cold-water immersion (CWI) accelerates heat loss, thus challenging thermoregulation during immersion. It is not known whether the acute pharmacological activation of BAT can aid thermoregulation during a progressive CWI challenge. We tested the hypothesis that acute MIRA ingestion would increase markers of BAT activation, mitigate the reduction in body temperature, and extend CWI duration during a progressive CWI challenge vs. placebo (PLA). Methods: 12 healthy adults (age: 25±6 y; BMI: 26±5 kg/m 2 , body fat: 27±5%, 6 women) completed two, double-blind, randomized study visits: ingestion of 100 mg of MIRA or PLA. 30 min after ingestion, participants rested in an empty water immersion tank. Following baseline measures, 35°C water rapidly filled the tank up to the sternum. The temperature of the water was progressively cooled by 2.5°C every 15 min until reaching 10°C, where it was held constant for up to 240 min of total immersion time. Participants were asked to remain in the water for as long as possible or complete 240 min of immersion. O 2 consumption (VO 2 ; ml/kg/min), CO 2 production (VCO 2 ; ml/kg/min), and respiratory exchange ratio (RER) were measured using indirect calorimetry. BAT activity was estimated via supraclavicular skin temperature (T sc ; infrared thermography) and expressed relative to shoulder skin temperature. Mean skin temperature (T sk ; 12 sites), and rectal temperature (T c ) were measured and used to calculate mean body temperature (T b ). Shivering was assessed via mechanomyography (MMG; 3 tri-axial accelerometers) and the bedside shivering scale (BSS; 0 = no shivering, 3=severe shivering). Perceptual measures of thermal discomfort (1=comfortable, 4=very uncomfortable) and sensation (1=cold, 7=hot) were also measured. Data were captured at 15 min intervals up until the last common timepoint for all CWIs (i.e., 60 min). Values are reported as mean ± SD. Results: Total CWI duration was greater following MIRA ingestion vs PLA (127.1±55.0 vs 142.2±44.3 min; p =0.050). VO 2 (PLA: 7.2±3.1 vs MIRA: 7.6±3.3 ml/kg/min; condition effect p =0.579), VCO 2 (PLA: 6.2±2.8 vs MIRA: 6.5±2.9 ml/kg/min; condition effect p =0.559), and RER (PLA: 0.85±0.07 vs MIRA: 0.86±0.07; condition effect p =0.825) did not differ between conditions. MIRA elicited greaterT sc (PLA: 36.0 ± 0.1 vs MIRA: 36.3±0.4°C; condition effect p =0.014) and relative T sc (PLA: 1.5± 0.4 vs MIRA: 1.9±0.4°C; condition effect p =0.003) vs PLA. MIRA caused higher T sk (PLA: 29.9± 2.3 vs MIRA: 31.2±1.6°C; condition effect p =0.013) and T b (PLA: 34.5±0.8 vs MIRA: 34.9±0.5°C; condition effect p =0.015) vs PLA, but T c did not differ between conditions (PLA: 37.0±0.2 vs MIRA: 37.0±0.2°C; condition effect p =0.812). MMG (PLA: 0.7±0.1 vs MIRA: 0.7±0.1 cm 2 ; condition effect p =0.762), BSS (PLA: 0.1±0.3 vs MIRA: 0.1±03; condition effect p =0.777), thermal discomfort (PLA: 1.6±0.7 vs MIRA: 1.5±0.6; condition effect p =0.530), and thermal sensation (PLA: 3.5±1.1 vs MIRA: 3.4±1.1; condition effect p =0.363) did not differ between conditions. Conclusion: Our data indicate that acute ingestion of MIRA extended the duration of immersion during a progressive CWI challenge and mitigated reductions in body temperature. Further, MIRA ingestion augmented markers of BAT activity, suggesting that the pharmacological stimulation of BAT might improve resiliency during CWI. Funded by: Office of Naval Research N00014-21-1-2276 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.