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PMID: 19356713 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.

Cell metabolism ·Vol. 9 ·No. 4 ·2009-04-00 ·Pages 311-26

Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP

Abstract

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.

MeSH Terms
Amino Acids, Branched-Chain/metabolism Animals Cytokines/metabolism Demography Dietary Fats/administration & dosage,pharmacology Dietary Supplements Feeding Behavior/drug effects Female Hormones/metabolism Humans Insulin/metabolism Insulin Resistance/physiology Male Mass Spectrometry Metabolome Metabolomics Middle Aged Obesity/metabolism Rats Rats, Wistar Signal Transduction/drug effects Thinness/metabolism
Chemicals
Amino Acids, Branched-Chain Cytokines Dietary Fats Hormones Insulin
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Newgard Christopher B
Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710, USA. [email protected]
An Jie
Bain James R
Muehlbauer Michael J
Stevens Robert D
Lien Lillian F
Haqq Andrea M
Shah Svati H
Arlotto Michelle
Slentz Cris A
Rochon James
Gallup Dianne
Ilkayeva Olga
Wenner Brett R
Yancy William S
Eisenson Howard
Musante Gerald
Surwit Richard S
Millington David S
Butler Mark D
Svetkey Laura P
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Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1932-7420
DOI
10.1016/j.cmet.2009.02.002
Email
[email protected]
Published
2009-04-00
Pages
311-26
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC3640280
Subset
IM
Grants
NCRR NIH HHS · 1K23-RR-021979 · United States
NIDDK NIH HHS · P01 DK058398 · United States
NIDDK NIH HHS · P01 DK058398-08 · United States
NHLBI NIH HHS · U01 HL068734 · United States
NHLBI NIH HHS · U01 HL068734-02 · United States
NCRR NIH HHS · K23 RR021979-04 · United States
NCRR NIH HHS · K23 RR021979 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1016/j.cmet.2009.02.002 PMC Full Text View journal details
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