The role of branched-chain amino acids and their downstream metabolites in mediating insulin resistance

Abstract

Elevated levels of circulating branched-chain amino acids (BCAAs) and their associated metabolites have been strongly linked to insulin resistance and type 2 diabetes. Despite extensive research, the precise mechanisms linking increased BCAA levels with these conditions remain elusive. In this review, we highlight the key organs involved in maintaining BCAA homeostasis and discuss how obesity and insulin resistance disrupt the intricate interplay among these organs, thus affecting BCAA balance. Additionally, we outline recent research shedding light on the impact of tissue-specific or systemic modulation of BCAA metabolism on circulating BCAA levels, their metabolites, and insulin sensitivity, while also identifying specific knowledge gaps and areas requiring further investigation. Finally, we summarize the effects of BCAA supplementation or restriction on obesity and insulin sensitivity.

Keywords: BCAAs; BCKAs; insulin resistance; obesity; type 2 diabetes.

FIGURE 1

Overview of branched-chain amino acid catabolism pathway. The initial and shared step in the catabolism of all three branched-chain amino acids (BCAAs) - leucine (Leu), isoleucine (Ile), and valine (Val) - involves the reversible transamination of BCAAs to produce branched-chain alpha-ketoacids (BCKAs). Specifically, Leu yields α-ketoisocaproate (KIC), Ile yields α-keto-ß-methylvalerate (KMV), and Val yields α-ketovalerate (KIV). This transamination process is catalyzed by two distinct isoforms of branched-chain amino acid aminotransferase (BCAT): the cytosolic isoform (BCATc/BCAT1, encoded by the Bcat1 gene), predominantly found in the central nervous system and peripheral nerves, and the mitochondrial isoform (BCATm/BCAT2, encoded by the Bcat2 gene), primarily located in the mitochondria of most nonneuronal tissues. Subsequently, all three BCKAs (KIC, KMV, and KIV) undergo irreversible oxidative decarboxylation, facilitated by the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, which serves as the rate-limiting enzyme in BCAA oxidation. The BCKDH complex comprises of three components: E1 (encoded by Bckdha and Bckdhb genes), E2 (encoded by Dbt gene), and E3 (encoded by Dld gene). The activity of the BCKDH complex is tightly regulated by BCKDH kinase (BCKDK), which phosphorylates E1 of the BCKDH complex and inhibits its activity (i.e., inhibiting BCAA oxidation), whereas protein phosphatase 2Cm (PP2Cm) dephosphorylates E1 of the BCKDH complex and activates its activity (i.e., activating BCAA oxidation). Post-decarboxylation, each BCKA follows a distinct metabolic pathway, generating acyl-CoA derivatives (isovaleryl-CoA from KIC, 2-methylbutyryl-CoA from KMV, and isobutyryl-CoA from KIV) and various downstream metabolites. These metabolites include critical metabolic intermediates for the TCA cycle, such as acetyl-CoA or succinyl-CoA, as well as acetoacetate, metabolic end products of Leu catabolism, 3-hydroxyisobutyrate (3-HIB), a downstream metabolite of Val that stimulates fatty acid uptake, and monomethyl branched-chain fatty acids (mmBCFAs), adipocyte-specific metabolites derived from mitochondrial BCAA catabolism, namely, propionyl-CoA.

FIGURE 2

Potential targets for correcting alterations in BCAA metabolism to treat insulin resistance. In animal models of obesity and insulin resistance, mounting evidence suggests that BCKA accumulation, rather than BCAA accumulation, impairs glucose homeostasis and decreases insulin sensitivity. Therefore, one approach to lowering BCKA levels would be to inhibit BCAT2 or enhance BCAA oxidation activity using a BCKDK inhibitor. BCAA, branched-chain amino acid; BCKA, branched-chain α-keto acid; BCAT2, branched-chain amino acid aminotransferase 2; BCKDH, branched-chain α-ketoacid dehydrogenase complex; BCKDK, BCKDH kinase; PP2Cm, protein phosphatase 2Cm; BCAT2i, BCAT2 inhibitor; BCKDKi, BCKDK inhibitor.