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Oud ma 27 apr 2009, 20:51   #1
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A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

Christopher B. Newgard1,2,3,,,Jie An1,3,James R. Bain1,Michael J. Muehlbauer1,Robert D. Stevens1,Lillian F. Lien1,2,Andrea M. Haqq1,4,Svati H. Shah2,Michelle Arlotto1,Cris A. Slentz2,James Rochon5,Dianne Gallup5,Olga Ilkayeva1,Brett R. Wenner1,William S. Yancy2,Howard Eisenson6,Gerald Musante2,Richard S. Surwit7,David S. Millington1,4,Mark D. Butler1andLaura P. Svetkey1,2

1 Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710, USA
2 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
4 Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
5 Department of Biostatistics and Informatics, Duke University Medical Center, Durham, NC 27710, USA
6 Department of Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA
7 Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA


Summary
Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.
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