Changes in circulating bile acid levels during cold exposure are associated with brown adipose tissue in humans: a secondary analysis from the ACTIBATE study

Abstract

Cold exposure activates brown adipose tissue (BAT), a therapeutic target to mitigate cardiometabolic diseases. Emerging evidence suggests that bile acids may influence BAT activity through metabolic and endocrine signaling pathways. Characterizing changes in circulating bile acids during cold exposure may uncover new pathways to improve metabolic health in humans. We analysed 56 young (21.7 ± 2.3 years old), sedentary adults (43 women, 77%) from the ACTIBATE cohort (NCT02365129) before the intervention in whom plasma samples were available for bile acid analyses. Eighteen plasma bile acid species were analyzed using liquid chromatography-tandem mass spectrometry before (i.e., baseline), 60, and 120 min during a personalized cooling protocol. BAT volume, activity, and radiodensity were assessed via 18F-fluorodeoxyglucose positron emission tomography-computed tomography scan (18F-FDG PET-CT) at the end of the cooling protocol. During the 2-hour cold exposure, plasma levels of total, secondary, and conjugated bile acids decreased by 24–30% (all P < 0.001). In normal-weight participants, most reductions remained significant after adjustment for PET-CT time, and glycolithocholic acid (GLCA) showed consistent positive associations with BAT volume and glucose uptake, as well as an inverse association with radiodensity (|r|≤0.41, adj. FDR ≤ 0.25; R ≤ 0.34, P ≤ 0.038 in adjusted regression models). In participants with overweight or obesity, most bile-acid changes lost statistical significance after adjustment for PET-CT time, although lithocholic acid and its sulfated derivative remained positively correlated with BAT radiodensity (|r|≤0.53; adj. FDR ≤ 0.25). Acute cold exposure is associated with changes in circulating bile acids in humans, with patterns differing by body-weight status. In normal-weight individuals, GLCA displayed consistent associations with BAT volume and glucose uptake, suggesting a possible link between bile acid and BAT activation. Further studies are needed to confirm these observations and to clarify the physiological relevance of bile acid signaling in human thermogenic adaptation.