A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.
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.
Newgard
Christopher B
CB
Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710, USA. newga002@mc.duke.edu
An
Jie
J
Bain
James R
JR
Muehlbauer
Michael J
MJ
Stevens
Robert D
RD
Lien
Lillian F
LF
Haqq
Andrea M
AM
Shah
Svati H
SH
Arlotto
Michelle
M
Slentz
Cris A
CA
Rochon
James
J
Gallup
Dianne
D
Ilkayeva
Olga
O
Wenner
Brett R
BR
Yancy
William S
WS
Eisenson
Howard
H
Musante
Gerald
G
Surwit
Richard S
RS
Millington
David S
DS
Butler
Mark D
MD
Svetkey
Laura P
LP
D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003710:Demography; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D019587:Dietary Supplements; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013851:Thinness / Q000378:metabolism*
D000597:Amino Acids, Branched-Chain; D016207:Cytokines; D004041:Dietary Fats; D006728:Hormones; D007328:Insulin