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Review
. 2012 May 2;15(5):606-14.
doi: 10.1016/j.cmet.2012.01.024.

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

Christopher B Newgard  1
Affiliations
Review

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

Christopher B Newgard. Cell Metab. .

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.

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Figures

Figure 1
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
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
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.
See this image and copyright information in PMC

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