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.
Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710, USA. newga002@mc.duke.edu
Christopher B
CB
Newgard
Jie
J
An
James R
JR
Bain
Michael J
MJ
Muehlbauer
Robert D
RD
Stevens
Lillian F
LF
Lien
Andrea M
AM
Haqq
Svati H
SH
Shah
Michelle
M
Arlotto
Cris A
CA
Slentz
James
J
Rochon
Dianne
D
Gallup
Olga
O
Ilkayeva
Brett R
BR
Wenner
William S
WS
Yancy
Howard
H
Eisenson
Gerald
G
Musante
Richard S
RS
Surwit
David S
DS
Millington
Mark D
MD
Butler
Laura P
LP
Svetkey
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