Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.
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 (SI, 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.
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Endocrinology Department, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona 08950, Spain. Electronic address: clerin@fsjd.org.
Carles
C
Lerin
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
Allison B
AB
Goldfine
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Tanner
T
Boes
Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Manway
M
Liu
Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Simon
S
Kasif
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Jonathan M
JM
Dreyfuss
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
Ana Luisa
AL
De Sousa-Coelho
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Grace
G
Daher
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Irini
I
Manoli
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Justin R
JR
Sysol
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
Elvira
E
Isganaitis
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Niels
N
Jessen
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Laurie J
LJ
Goodyear
Metabolon, Inc., Durham, NC 27723, USA.
Kirk
K
Beebe
Metabolon, Inc., Durham, NC 27723, USA.
Walt
W
Gall
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Charles P
CP
Venditti
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address: mary.elizabeth.patti@joslin.harvard.edu.
Mary-Elizabeth
ME
Patti
BCAA; Fatty acid oxidation; Insulin sensitivity; TCA cycle
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