title: Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner.
abstract: 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.
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Mahshid
authors.initials: M
authors.lastname: Moghei
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Pegah
authors.initials: P
authors.lastname: Tavajohi-Fini
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Beatty
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Ontario, Canada oadegoke@yorku.ca.
authors.forename: Olasunkanmi A J
authors.initials: OA
authors.lastname: Adegoke
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D007651:Keto Acids / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D026901:Membrane Transport Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D046912:Multiprotein Complexes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism
chemical_list: D000596:Amino Acids; D007328:Insulin; D007651:Keto Acids; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D046912:Multiprotein Complexes; C013082:alpha-ketoisocaproic acid; D000637:Transaminases; C000629171:Bcat2 protein, rat; C019798:branched-chain-amino-acid transaminase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D005947:Glucose
keywords: glucose transport; insulin resistance; leucine; mTORC1; α-ketoisocaproic acid