Interplay between lipids and branched-chain amino acids in development of insulin resistance

Abstract

Fatty acids (FA) and FA-derived metabolites have long been implicated in the development of insulin resistance and type 2 diabetes. Surprisingly, application of metabolomics technologies has revealed that branched-chain amino acids (BCAA) and related metabolites are more strongly associated with insulin resistance than many common lipid species. Moreover, the BCAA-related signature is predictive of incident diabetes and intervention outcomes and uniquely responsive to therapeutic interventions. Nevertheless, in animal feeding studies, BCAA supplementation requires the background of a high-fat diet to promote insulin resistance. This Perspective develops a model to explain how lipids and BCAA may synergize to promote metabolic diseases.

Figure 1. Pathways of branched-chain amino acid catabolism

Shown in blue are the reactions that produce metabolites found in the BCAA-related principal component that associates with insulin resistance and other metabolic diseases.

Figure 2. Acylcarnitines in skeletal muscle in rats fed on various diets for 12 weeks

SC, standard chow, SC/BCAA, standard chow supplemented with branched-chain amino acids (Val, Leu, Ile); HF, high fat diet (35% calories from fat); HF/BCAA, HF diet supplemented with branched-chain amino acids. Inset. C3 and C5 acylcarnitines in rats fed on various diets. Data adapted from Newgard, et al., 2009.

Figure 3. Schematic working model of potential cross-talk between lipids and BCAA in development of obesity-related insulin resistance

See text for details. “Anaplerosis” refers to repletion or filling up of TCA cycle intermediates via entry points other than acetyl CoA. TG, triglyceride; IMTG, intramyocellular triglyceride; IR, insulin receptor.