Endocrine Abstracts

JOINT2737

Background/Objective: Brown adipose tissue (BAT) plays a crucial role in thermoregulation. Upon cold exposure, the sympathetic nervous system releases norepinephrine, which activates β-adrenergic receptors (β-AR) on brown adipocytes. This activation stimulates lipolysis, leading to the release of free fatty acids that serve both as activators of uncoupling protein 1 (UCP1) and as substrates for mitochondrial oxidation, thereby generating heat. Recent research has indicated that β₂-AR stimulation could activate human BAT. Here, we analysed the changes in lipidome in response to cold-exposure and β₂-adrenergic stimulation with the selective agonist fenoterol.

Methods: We performed a cross-over, randomized trial in twelve healthy volunteers (seven men and five women). We determined resting energy expenditure (REE) using indirect calorimetry once before and after a mild cold stimulus and in a further visit before and after a continuous fenoterol injection (145 µg). Both interventions were performed over 2 hours. Blood sampling to obtain serum for later metabolome analysis by gas chromatography-mass spectrometry (GC-MS) was performed at every visit.

Results: Our study demonstrates that both fenoterol and mild cold exposure significantly increased REE in humans: before fenoterol 1502±281 kcal/24h, after fenoterol 1860±305 kcal/24h (P < 0.0001); before cold 1516±347 kcal/24, after cold 1712±270 kcal/24h (P = 0.02). Both interventions led to a distinct change in plasma lipid levels. Specifically, fenoterol infusion induced a marked increase in free fatty acid (FA) levels; with FA 18:3 (_log2FC = 1.21, P = 4 x 10^-8)), FA 20:3 (_log2FC = 0.76, P = 1.2 x10^-7), FA 14:0 (_log2FC = 0.82, P = 5.6 x 10^-7), FA 20:2 (_log2FC = 0.73, P = 7.3 x 10^-7) and FA 12:0 (_log2FC = 0.78, P = 8 x 10^-7). In contrast, cold exposure led to a more nuanced increase in FA levels; with FA 18:3 (_log2FC = 0.46, P = 0.007), FA 14:0 (_log2FC = 0.34, P = 0.008) and FA 22:6 (_log2FC = 0.44, P = 0.009). In contrast to fenoterol, the most regulated lipids after cold exposure were lysophosphatidylcholines which were reduced; LPC 18:2 (log2FC = -0.29, P = 7.7x10^-5), LPC 18:1 (_log2FC = -0.18, P = 2.1x10^-4) and LPC 18:3 (_log2FC = -0.15, P = 2.8x10^-4).

Conclusion: Both cold exposure and stimulation of the β₂-AR increase lipolysis and REE in humans. Our findings indicate that enhanced lipolysis is a key mechanism driving β₂-AR-stimulated thermogenesis. However, the distinct lipidomic profile points towards different molecular mechanisms in response to cold.