The history of β-aminoisobutyric acid: from a waste metabolite to a druggable compound for metabolic disease. A narrative review.

β-Αminoisobutyric acid (BAIBA) is a β-amino acid discovered in the 1950's as a waste product of valine and thymine biotransformation. In the early 2000s, we discovered that BAIBA could promote hepatic fatty acid oxidation (FAO) and ketogenesis, reduce fatty liver and body fatness, and improve glucose intolerance in obese mice, in a leptin-dependent manner. A few years later, another team reported that BAIBA was a myokine acting on white adipocytes to induce browning and confirmed that it could promote hepatic FAO. Since then, other researchers have borne out that BAIBA is a bona fide myokine whose circulating levels could serve as a biomarker in certain metabolic states and diseases. Moreover, further investigations showed that BAIBA could act on cells other than hepatocytes and adipocytes, including osteocytes, endothelial and neuronal cells, myocytes, and cardiomyocytes. In these cells, BAIBA exerts its metabolic and cytoprotective effects via different signaling pathways involving, for instance, AMP-activated protein kinase, protein kinase A, peroxisome proliferator-activated receptor γ coactivator 1, and peroxisome proliferator-activated receptors α and δ. Overall, these studies provide strong evidence that BAIBA presents favorable effects on different conditions associated with obesity and diabetes. This could make BAIBA a potential druggable compound since it presents an apparent good safety profile, while derivatives are currently being developed to enhance BAIBA biodistribution. This narrative review aims to tell the fascinating history of BAIBA, which spans 75 years.