Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner.

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Mahshid Moghei, Pegah Tavajohi-Fini, Brendan Beatty, Olasunkanmi A J Adegoke

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Mahshid Moghei: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
Pegah Tavajohi-Fini: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
Brendan Beatty: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
Olasunkanmi A J Adegoke: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada oadegoke@yorku.ca.

PMID: 27488662 DOI: 10.1152/ajpcell.00062.2016

Although leucine has many positive effects on metabolism in multiple tissues, elevated levels of this amino acid and the other branched-chain amino acids (BCAAs) and their metabolites are implicated in obesity and insulin resistance. While some controversies exist about the direct effect of leucine on insulin action in skeletal muscle, little is known about the direct effect of BCAA metabolites. Here, we first showed that the inhibitory effect of leucine on insulin-stimulated glucose transport in L6 myotubes was dampened when other amino acids were present, due in part to a 140% stimulation of basal glucose transport (P < 0.05). Importantly, we also showed that α-ketoisocaproic acid (KIC), an obligatory metabolite of leucine, stimulated mTORC1 signaling but suppressed insulin-stimulated glucose transport (-34%, P < 0.05) in an mTORC1-dependent manner. The effect of KIC on insulin-stimulated glucose transport was abrogated in cells depleted of branched-chain aminotransferase 2 (BCAT2), the enzyme that catalyzes the reversible transamination of KIC to leucine. We conclude that although KIC can modulate muscle glucose metabolism, this effect is likely a result of its transamination back to leucine. Therefore, limiting the availability of leucine, rather than those of its metabolites, to skeletal muscle may be more critical in the management of insulin resistance and its sequelae.

glucose transport insulin resistance leucine mTORC1 α-ketoisocaproic acid

Biochem Biophys Res Commun. 2002 Dec 20;299(5):693-6 [PMID: 12470633]

J Biol Chem. 2001 Oct 12;276(41):38052-60 [PMID: 11498541]

Am J Cardiol. 2002 Sep 5;90(5A):11G-18G [PMID: 12231074]

Mol Cell Biochem. 2010 Nov;344(1-2):43-53 [PMID: 20628794]

Biochimie. 2005 Jan;87(1):99-109 [PMID: 15733744]

Diabetes. 2001 Feb;50(2):353-60 [PMID: 11272147]

Nature. 2013 Nov 7;503(7474):59-66 [PMID: 24201279]

Ann Intern Med. 2015 Feb 3;162(3):167-74 [PMID: 25643304]

Physiol Rep. 2014 Jul 04;2(7):null [PMID: 24997070]

Mediators Inflamm. 2010;2010:453892 [PMID: 20182627]

Eur J Clin Nutr. 2014 Sep;68(9):973-9 [PMID: 24986822]

Cell Metab. 2009 Apr;9(4):311-26 [PMID: 19356713]

Nat Rev Endocrinol. 2014 Dec;10(12):723-36 [PMID: 25287287]

World J Diabetes. 2010 May 15;1(2):36-47 [PMID: 21537426]

Med Sci Sports Exerc. 2015 Mar;47(3):547-55 [PMID: 25026454]

J Am Coll Nutr. 2004 Oct;23(5):373-85 [PMID: 15466943]

Diabetologia. 2016 Mar;59(3):592-603 [PMID: 26733005]

Cell Metab. 2007 Sep;6(3):181-94 [PMID: 17767905]

J Nutr. 2006 Feb;136(2):533S-537S [PMID: 16424142]

J Sports Med Phys Fitness. 2014 Aug;54(4):373-82 [PMID: 25034542]

Diabetes. 2015 Jan;64(1):49-59 [PMID: 25071024]

Am J Clin Nutr. 2015 Oct;102(4):820-7 [PMID: 26289436]

Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1552-63 [PMID: 17925455]

PLoS One. 2011;6(6):e21187 [PMID: 21731668]

Am J Clin Nutr. 2014 Feb;99(2):276-86 [PMID: 24284442]

Pediatr Obes. 2013 Feb;8(1):52-61 [PMID: 22961720]

Annu Rev Nutr. 2009;29:21-41 [PMID: 19400750]

Am J Physiol Endocrinol Metab. 2011 Jun;300(6):E986-92 [PMID: 21406616]

Nutr Metab Cardiovasc Dis. 2009 Oct;19(8):548-54 [PMID: 19179060]

J Biol Chem. 2010 Oct 29;285(44):33718-26 [PMID: 20736162]

Diabetologia. 2010 Jul;53(7):1270-87 [PMID: 20361178]

J Nutr. 2010 Aug;140(8):1418-24 [PMID: 20534881]

Br J Nutr. 2012 Aug;108 Suppl 2:S105-12 [PMID: 23107521]

J Clin Invest. 2006 Jul;116(7):1793-801 [PMID: 16823477]

J Appl Physiol (1985). 2010 Feb;108(2):274-82 [PMID: 19940100]

J Appl Physiol (1985). 2011 Jul;111(1):163-9 [PMID: 21527668]

Obesity (Silver Spring). 2014 Dec;22(12):2570-8 [PMID: 25251340]

Diabetes. 2015 May;64(5):1555-63 [PMID: 25475435]

Adv Nutr. 2011 Nov;2(6):445-56 [PMID: 22332087]

Nature. 2004 Sep 9;431(7005):200-5 [PMID: 15306821]

Diabetologia. 2015 Sep;58(9):2133-43 [PMID: 26058503]

Amino Acids. 2014 Aug;46(8):1971-9 [PMID: 24806638]

Metabolism. 2009 Oct;58(10):1489-95 [PMID: 19586643]

Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R673-80 [PMID: 18094066]

J Clin Invest. 1995 Aug;96(2):811-21 [PMID: 7635976]

Annu Rev Nutr. 2007;27:293-310 [PMID: 17666010]

Am J Clin Nutr. 2008 May;87(5):1558S-1561S [PMID: 18469287]

Metabolism. 2015 Nov;64(11):1582-91 [PMID: 26385052]

Mol Endocrinol. 2000 Jun;14(6):783-94 [PMID: 10847581]

Am J Physiol Endocrinol Metab. 2002 Oct;283(4):E824-35 [PMID: 12217901]

Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E854-63 [PMID: 12812918]

Diabetologia. 2000 Oct;43(10):1257-65 [PMID: 11079744]

Amino Acids

Animals

Biological Transport

Cells, Cultured

Glucose

Insulin

Insulin Resistance

Keto Acids

Leucine

Mechanistic Target of Rapamycin Complex 1

Membrane Transport Proteins

Mitochondrial Proteins

Monocarboxylic Acid Transporters

Multiprotein Complexes

Muscle Fibers, Skeletal

Muscle, Skeletal

Rats

TOR Serine-Threonine Kinases

Transaminases