17
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective

          Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear.

          Methods

          To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (S I, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis.

          Results

          Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding.

          Conclusions

          Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.

          Highlights

          • Human insulin resistance is associated with perturbed muscle BCAA metabolism.

          • Experimental modulation of BCAA metabolic flux alters fatty acid oxidation in vitro.

          • Mut heterozygosis leads to increased body weigh and muscle TAG accumulation in mice.

          Related collections

          Most cited references39

          • Record: found
          • Abstract: not found
          • Article: not found

          Plasma amino acid levels and insulin secretion in obesity.

            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults

            OBJECTIVE Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults. RESEARCH DESIGN AND METHODS Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood. RESULTS Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination. CONCLUSIONS Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism.

              Elevations in branched-chain amino acids (BCAAs) in human obesity were first reported in the 1960s. Such reports are of interest because of the emerging role of BCAAs as potential regulators of satiety, leptin, glucose, cell signaling, adiposity, and body weight (mTOR and PKC). To explore loss of catabolic capacity as a potential contributor to the obesity-related rises in BCAAs, we assessed the first two enzymatic steps, catalyzed by mitochondrial branched chain amino acid aminotransferase (BCATm) or the branched chain alpha-keto acid dehydrogenase (BCKD E1alpha subunit) complex, in two rodent models of obesity (ob/ob mice and Zucker rats) and after surgical weight loss intervention in humans. Obese rodents exhibited hyperaminoacidemia including BCAAs. Whereas no obesity-related changes were observed in rodent skeletal muscle BCATm, pS293, or total BCKD E1alpha or BCKD kinase, in liver BCKD E1alpha was either unaltered or diminished by obesity, and pS293 (associated with the inactive state of BCKD) increased, along with BCKD kinase. In epididymal fat, obesity-related declines were observed in BCATm and BCKD E1alpha. Plasma BCAAs were diminished by an overnight fast coinciding with dissipation of the changes in adipose tissue but not in liver. BCAAs also were reduced by surgical weight loss intervention (Roux-en-Y gastric bypass) in human subjects studied longitudinally. These changes coincided with increased BCATm and BCKD E1alpha in omental and subcutaneous fat. Our results are consistent with the idea that tissue-specific alterations in BCAA metabolism, in liver and adipose tissue but not in muscle, may contribute to the rise in plasma BCAAs in obesity.
                Bookmark

                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                06 August 2016
                October 2016
                06 August 2016
                : 5
                : 10
                : 926-936
                Affiliations
                [1 ]Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
                [2 ]Harvard Medical School, Boston, MA 02215, USA
                [3 ]Endocrinology Department, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona 08950, Spain
                [4 ]Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
                [5 ]Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
                [6 ]Metabolon, Inc., Durham, NC 27723, USA
                Author notes
                []Corresponding author. Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.Joslin Diabetes CenterOne Joslin PlaceBostonMA02215USA mary.elizabeth.patti@ 123456joslin.harvard.edu
                [∗∗ ]Corresponding author. Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona 08950, Spain.Institut de Recerca Pediàtrica Hospital Sant Joan de DéuJoslin Diabetes CenterBarcelona08950Spain clerin@ 123456fsjd.org
                [7]

                Present address: Saffron Technology, Cary, NC 27513, USA.

                Article
                S2212-8778(16)30115-6
                10.1016/j.molmet.2016.08.001
                5034611
                27689005
                bf2716f5-4e30-4022-aabe-91a28936c041
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Original Article

                insulin sensitivity,bcaa,fatty acid oxidation,tca cycle
                insulin sensitivity, bcaa, fatty acid oxidation, tca cycle

                Comments

                Comment on this article