Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with
obesity and are associated with worse metabolic health and future
insulin resistance or
type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves
leucine-mediated activation of the
mammalian target of rapamycin complex 1 (
mTORC1), which results in uncoupling of
insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell
mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively,
insulin resistance might promote aminoacidaemia by increasing the protein degradation that
insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in
obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for
obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific
branched chain ketoacid dehydrogenase complex activity have been detected in animal models of
obesity and T2DM.