Endocrine Abstracts

JOINT3339

Background: Brown adipose tissue (BAT) may directly dissipate energy from lipids and carbohydrates into heat and its activity is associated with a favorable metabolic phenotype in human adults. In rodents, BAT is activated by the sympathetic nervous system and its transmitter norepinephrine via the α3-adrenoreceptor (α3-AR). In humans stimulation of the α3-AR even with high doses of the selective agonist Mirabegon leads to a rather weak activation of BAT as compared to a cold stimulus. In vitro studies in cell lines from human BAT and one human study have pointed towards the α2-AR as a possible activator of human BAT. Here, we studied the effect of the potent and selective α2-AR agonist fenoterol on human energy expenditure (EE) and BAT activity.

Methods: Healthy normal weight volunteers were initially screened for cold-induced thermogeneis. Twelve individuals with cold-induced thermogenesis of >5% of resting energy expenditure were included. They received the following interventions over two hours in random order: A) standardized mild cold stimulus; B) intravenous infusion of the selective α2-agonist Fenoterol. EE was measured continously with indirect calorimetry, skin and core temperature were recorded and BAT activity was quantified in the supraclavicular BAT depot by 18F-FDG-PET/CT after each intervention.

Results: Resting EE at baseline was 1516±347 kcal/24h before cold-exposure and 1502±281 kcal/24h before Fenoterol. Cold exposure resulted in a mean increase in EE of 195 kcal/24h (P = 0.044 vs. baseline) and Fenoterol infusion increased EE by 358 kcal/24h (P < 0.0001). The mean standardized uptake value (SUVmean) of supraclavicular BAT was 3.06 (IQR 2.19;3.64) g/ml after cold exposure but only 1.66 g/ml [1.63;1.70] after Fenoterol infusion. Correspondingly, the active BAT volume was 90 (26;190) ml vs. 3 (1;16) ml. Supraclavicular temperature increased promptly in response to cold, but not after fenoterol. Fenoterol immediately and strongly increased levels of circulating fatty acids and glycerol, while triglyceride levels remained stable. A slower lipolytic response occurred during cold stimulation. In both interventions the lipolytic response paralleled the kinetics of EE during the respective visit. Only fenoterol increased serum-glucose, insulin, and lactate. In another cohort of healthy individuals, expression of the α3-AR but not of the α2-AR was correlated to the level of UCP1, the hallmark of brown adipocytes.

Conclusion: We found no evidence that α2-ARs play a major role in activation of human BAT. A reason for the observed fenoterol-induced increase in REE could be futile metabolic cycles e.g. lipid cycling in skeletal muscle or white adipose tissue.