Amino acids contribute to adaptive thermogenesis. New insights into the mechanisms of action of recent drugs for metabolic disorders are emerging.

Adaptive thermogenesis is the heat production by muscle contractions (shivering thermogenesis) or brown adipose tissue (BAT) and beige fat (non-shivering thermogenesis) in response to external stimuli, including cold exposure. BAT and beige fat communicate with peripheral organs and the brain through a variegate secretory and absorption processes - controlling adipokines, microRNAs, extracellular vesicles, and metabolites - and have received much attention as potential therapeutic targets for managing obesity-related disorders. The sympathetic nervous system and norepinephrine-releasing adipose tissue macrophages (ATM) activate uncoupling protein 1 (UCP1), expressed explicitly in brown and beige adipocytes, dissolving the electrochemical gradient and uncoupling tricarboxylic acid cycle and the electron transport chain from ATP production. Mounting evidence has attracted attention to the multiple effects of dietary and endogenously synthesised amino acids in BAT thermogenesis and metabolic phenotype in animals and humans. However, the mechanisms implicated in these processes have yet to be conclusively characterized. In the present review article, we aim to define the principal investigation areas in this context, including intestinal microbiota constitution, adipose autophagy modulation, and secretome and metabolic fluxes control, which lead to increased brown/beige thermogenesis. Finally, also based on our recent epicardial adipose tissue results, we summarise the evidence supporting the notion that the new dual and triple agonists of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptor - with never before seen weight loss and insulin-sensitizing efficacy - promote thermogenic-like amino acid profiles in BAT with robust heat production and likely trigger sympathetic activation and adaptive thermogenesis by controlling amino acid metabolism and ATM expansion in BAT and beige fat.