Interplay between lipids and branched-chain amino acids in development of insulin resistance - PubMed (original) (raw)

Review

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

Christopher B Newgard. Cell Metab. 2012.

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

PubMed Disclaimer

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.

Similar articles

Cited by

References

    1. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. Am. J. Physiol. 2009;296:E592–E602. - PMC - PubMed
    1. Bain JR, Stevens RD, Wenner BR, Ilkayeva O, Muoio DM, Newgard CB. Metabolomics applied to diabetes research: Moving from information to knowledge. Diabetes. 2009;58:2429–2443. - PMC - PubMed
    1. Boucher A, Lu D, Burgess S, Telemaque-Potts S, Jensen M, Mulder H, Wang M-Y, Unger RH, Sherry AD, Newgard CB. Mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and its reversal by an analogue of malate. J. Biol. Chem. 2004;279:27263–27271. - PubMed
    1. Clifton P. Diabetes: treatment of type 2 diabetes mellitus with bariatric surgery. Nature Rev. Endocrinol. 2010;6:191–193. - PubMed
    1. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312:927–930. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources