Endocrine Abstracts

Obesity is the leading preventable cause of morbidity and mortality worldwide. As a thermogenic organ, brown adipose tissue (BAT) holds promise as a pharmacological target for obesity and associated co-morbidities. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT and is activated by cold-induced sympathetic stimulation. It remains unclear whether human BAT activity is reduced in obesity and cardiometabolic disease. In addition, our understanding of human BAT regulation remains limited, in part due to interspecies differences between human and murine BAT. RNA sequencing of human brown and white adipocytes identified the serotonergic and parasympathetic systems as two candidate pathways that were prioritized for further investigation. I hypothesised that: (1) UCP1 expression in BAT was associated with favourable cardiometabolic risk factors; (2) the parasympathetic nervous system is a novel regulator of human BAT activity; (3) telotristat ethyl (a peripheral serotonin synthesis inhibitor) enhances human BAT and cardiometabolic health. To test these, I undertook several double-blinded placebo-controlled and case-control studies using techniques such as ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/MR, indirect calorimetry, thermal imaging and qPCR. (1) I demonstrated an inverse association between UCP1 expression in BAT (n=53 participants) but not WAT with ageing, adiposity, hypertension and insulin resistance. Additionally, UCP1 expression and ¹⁸F-FDG uptake by BAT were preserved in young obese adults. (2) Oxybutynin, a muscarinic acetylcholine receptor antagonist, inhibited ¹⁸F-FDG uptake by BAT by ~20% during mild cold exposure and suppressed cold-induced thermogenesis. (3) Contrary to the hypothesis, telotristat ethyl inhibited ¹⁸F-FDG uptake by BAT by ~25% and was deleterious to cardiometabolic health (suppressed cold-induced thermogenesis, reduced noradrenaline and increased cholesterol levels). Collectively, these studies demonstrated (1) an association between BAT dysfunction and adverse cardiometabolic profile, (2) the parasympathetic nervous system as a novel regulator of human BAT and (3) key interspecies differences in peripheral serotonin action on cardiometabolic health.