Branched chain amino acids—friend or foe in the control of energy substrate turnover and insulin sensitivity?

References

• Adams, S. H. 2011. Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state. Advances in Nutrition 2 (6):445–56. doi: 10.3945/an.111.000737.
   PubMed Web of Science ®Google Scholar
• Allam-Ndoul, B., F. Guénard, V. Garneau, O. Barbier, L. Pérusse, and M.-C. Vohl. 2015. Associations between branched chain amino acid levels, obesity and cardiometabolic complications. Integrative Obesity and Diabetes 1 (6):157–62. doi: 10.15761/IOD.1000134.
   Google Scholar
• Allman, B. R., E. C. Diaz, A. Andres, and E. Børsheim. 2020. Divergent changes in serum branched-chain amino acid concentrations and estimates of insulin resistance throughout gestation in healthy women. The Journal of Nutrition 150 (7):1757–64. doi: 10.1093/jn/nxaa096.
   PubMed Web of Science ®Google Scholar
• Allman, B. R., B. J. Spray, K. E. Mercer, A. Andres, and E. Børsheim. 2021. Markers of branched-chain amino acid catabolism are not affected by exercise training in pregnant women with obesity. Journal of Applied Physiology 130 (3):651–9. doi: 10.1152/japplphysiol.00673.2020.
   PubMed Web of Science ®Google Scholar
• Ananieva, E. A., C. G. Van Horn, M. R. Jones, and S. M. Hutson. 2017. Liver BCATm transgenic mouse model reveals the important role of the liver in maintaining BCAA homeostasis. The Journal of Nutritional Biochemistry 40 (February):132–40. doi: 10.1016/j.jnutbio.2016.10.014.
   PubMedGoogle Scholar
• Andersson-Hall, U., C. Gustavsson, A. Pedersen, D. Malmodin, L. Joelsson, and A. Holmäng. 2018. Higher concentrations of BCAAs and 3-HIB are associated with insulin resistance in the transition from gestational diabetes to type 2 diabetes. Journal of Diabetes Research 2018:4207067. doi:10.1155/2018/4207067
   PubMed Web of Science ®Google Scholar
• Arakawa, M., T. Masaki, J. Nishimura, M. Seike, and H. Yoshimatsu. 2011. The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice. Endocrine Journal 58 (3):161–70. doi: 10.1507/endocrj.K10E-221.
   PubMed Web of Science ®Google Scholar
• Arany, Z., and M. Neinast. 2018. Branched chain amino acids in metabolic disease. Current Diabetes Reports 18 (10):76. doi: 10.1007/s11892-018-1048-7.
   PubMed Web of Science ®Google Scholar
• Arrieta-Cruz, I., Y. Su, and R. Gutiérrez-Juárez. 2016. Suppression of endogenous glucose production by isoleucine and valine and impact of diet composition. Nutrients 8 (2):79. doi: 10.3390/nu8020079.
   PubMed Web of Science ®Google Scholar
• Aumoh’D, M. F., L. Matalqah, and Z. Al-Abdulla. 2020. Effects of oral branched-chain amino acids (BCAAs) intake on muscular and central fatigue during an incremental exercise. Journal of Human Kinetics 72 (1):69–78. doi: 10.2478/hukin-2019-0099.
   PubMed Web of Science ®Google Scholar
• Averous, J., S. Lambert-Langlais, F. Mesclon, V. Carraro, L. Parry, C. Jousse, A. Bruhat, A.-C. Maurin, P. Pierre, C. G. Proud, et al. 2016. GCN2 contributes to MTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism. Scientific Reports 6 (1):27698. doi: 10.1038/srep27698.
   PubMedGoogle Scholar
• Bai, J., E. Greene, W. Li, M. T. Kidd, and S. Dridi. 2015. Branched-chain amino acids modulate the expression of hepatic fatty acid metabolism-related genes in female broiler chickens. Molecular Nutrition & Food Research 59 (6):1171–81. doi: 10.1002/mnfr.201400918.
   PubMed Web of Science ®Google Scholar
• Bar-Peled, L., and D. M. Sabatini. 2014. Regulation of MTORC1 by amino acids. Trends in Cell Biology 24 (7):400–6. doi: 10.1016/j.tcb.2014.03.003.
   PubMed Web of Science ®Google Scholar
• Bassini, A., A. M. Magalhães-Neto, E. Sweet, A. Bottino, C. Veiga, M. B. Tozzi, M. B. Pickard, and L. C. Cameron. 2013. Caffeine decreases systemic urea in elite soccer players during intermittent exercise. Medicine & Science in Sports & Exercise 45 (4):683–90. doi: 10.1249/MSS.0b013e3182797637.
   PubMed Web of Science ®Google Scholar
• Bassini-Cameron, A., A. Monteiro, A. Gomes, J. P. S. Werneck-de-Castro, and L. Cameron. 2008. Glutamine protects against increases in blood ammonia in football players in an exercise intensity-dependent way. British Journal of Sports Medicine 42 (4):260–6. doi: 10.1136/bjsm.2007.040378.
   PubMed Web of Science ®Google Scholar
• Binder, E., F. J. Bermúdez-Silva, M. Elie, T. Leste-Lasserre, I. Belluomo, S. Clark, A. Duchampt, G. Mithieux, and D. Cota. 2014. Leucine supplementation modulates fuel substrates utilization and glucose metabolism in previously obese mice. Obesity 22 (3):713–20. doi: 10.1002/oby.20578.
   PubMed Web of Science ®Google Scholar
• Biswas, D., K. T. Dao, A. Mercer, A. M. Cowie, L. Duffley, Y. El Hiani, P. C. Kienesberger, and T. Pulinilkunnil. 2020. Branched-chain ketoacid overload inhibits insulin action in the muscle. The Journal of Biological Chemistry 295 (46):15597–621. doi: 10.1074/jbc.RA120.013121.
   PubMed Web of Science ®Google Scholar
• Biswas, D., L. Duffley, and T. Pulinilkunnil. 2019. Role of branched-chain amino acid-catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis. FASEB Journal 33 (8):8711–31. doi: 10.1096/fj.201802842RR.
   PubMed Web of Science ®Google Scholar
• Biswas, D., K. Tozer, K. T. Dao, L. J. Perez, A. Mercer, A. Brown, I. Hossain, A. M. Yip, C. Aguiar, H. Motawea, et al. 2020. Adverse outcomes in obese cardiac surgery patients correlates with altered branched-chain amino acid catabolism in adipose tissue and heart. Frontiers in Endocrinology 11:534. doi: 10.3389/fendo.2020.00534.
   PubMed Web of Science ®Google Scholar
• Blanchard, P.-G., R. J. Moreira, É. Castro, A. Caron, M. Côté, M. L. Andrade, T. E. Oliveira, M. Ortiz-Silva, A. S. Peixoto, F. A. Dias, et al. 2018. PPARγ is a major regulator of branched-chain amino acid blood levels and catabolism in white and brown adipose tissues. Metabolism 89:27–38. doi: 10.1016/j.metabol.2018.09.007.
   PubMed Web of Science ®Google Scholar
• Blouet, C., Y. Hwan Jo, X. Li, and G. J. Schwartz. 2009. Mediobasal hypothalamic leucine sensing regulates food intake through activation of a hypothalamus-brainstem circuit. The Journal of Neuroscience 29 (26):8302–11. doi: 10.1523/JNEUROSCI.1668-09.2009.
   PubMed Web of Science ®Google Scholar
• Boden, G., C. Homko, C. A. Barrero, T. P. Stein, X. Chen, P. Cheung, C. Fecchio, S. Koller, and S. Merali. 2015. Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men. Science Translational Medicine 7 (304):304re7. doi: 10.1126/scitranslmed.aac4765.
   PubMed Web of Science ®Google Scholar
• Bolster, D. R., M. Rahn, A. G. Kamil, L. T. Bristol, S. R. Goltz, H. J. Leidy, M. Blaze Mt, M. A. Nunez, E. Guo, J. Wang, et al. 2018. Consuming lower-protein nutrition bars with added leucine elicits postprandial changes in appetite sensations in healthy women. The Journal of Nutrition 148 (5):693–701. doi: 10.1093/jn/nxy023.
   PubMed Web of Science ®Google Scholar
• Borghi, L., R. Lugari, A. Montanari, P. Dall’Argine, G. F. Elia, V. Nicolotti, I. Simoni, A. Parmeggiani, A. Novarini, and A. Gnudi. 1985. Plasma and skeletal muscle free amino acids in type I, insulin-treated diabetic subjects. Diabetes 34 (8):812–815. doi: 10.2337/diab.34.8.812.
   PubMed Web of Science ®Google Scholar
• Boulangé, C. L., S. P. Claus, C. J. Chou, S. Collino, I. Montoliu, S. Kochhar, E. Holmes, S. Rezzi, J. K. Nicholson, M. E. Dumas, et al. 2013. Early metabolic adaptation in C57BL/6 mice resistant to high fat diet induced weight gain involves an activation of mitochondrial oxidative pathways. Journal of Proteome Research 12 (4):1956–1968. doi: 10.1021/pr400051s.
   PubMed Web of Science ®Google Scholar
• Boulet, M. M., G. Chevrier, T. Grenier-Larouche, M. Pelletier, M. Nadeau, J. Scarpa, C. Prehn, A. Marette, J. Adamski, and A. Tchernof. 2015. Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk. American Journal of Physiology-Endocrinology and Metabolism 309 (8):E736–E746. doi: 10.1152/ajpendo.00231.2015.
   PubMed Web of Science ®Google Scholar
• Bozadjieva Kramer, N., S. S. Evers, J. H. Shin, S. Silverwood, Y. Wang, C. F. Burant, D. A. Sandoval, and R. J. Seeley. 2020. The role of elevated branched-chain amino acids in the effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation. Cell Reports 33 (2):108239. doi: 10.1016/j.celrep.2020.108239.
   PubMed Web of Science ®Google Scholar
• Brietzke, S. A. 2015. Oral antihyperglycemic treatment options for type 2 diabetes mellitus. The Medical Clinics of North America 99 (1):87–106. doi: 10.1016/j.mcna.2014.08.012.
   PubMed Web of Science ®Google Scholar
• Bruckbauer, A., and M. B. Zemel. 2013. Synergistic effects of metformin, resveratrol, and hydroxymethylbutyrate on insulin sensitivity. Diabetes, Metabolic Syndrome and Obesity 6:93–102. doi: 10.2147/DMSO.S40840.
   PubMedGoogle Scholar
• Bruckbauer, A., and M. B. Zemel. 2014. Synergistic effects of polyphenols and methylxanthines with leucine on AMPK/sirtuin-mediated metabolism in muscle cells and adipocytes. PLoS One 9 (2):e89166. doi: 10.1371/journal.pone.0089166.
   PubMed Web of Science ®Google Scholar
• Cancello, R., J. Tordjman, C. Poitou, G. Guilhem, J. L. Bouillot, D. Hugol, C. Coussieu, A. Basdevant, A. B. Hen, P. Bedossa, et al. 2006. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55 (6):1554–1561. doi: 10.2337/db06-0133.
   PubMed Web of Science ®Google Scholar
• Chalvon-Demersay, T., J. Moro, P. C. Even, C. Chaumontet, D. Tomé, J. Averous, J. Piedcoq, C. Gaudichon, A.-C. Maurin, P. Fafournoux, et al. 2019. Liver GCN2 controls hepatic FGF21 secretion and modulates whole body postprandial oxidation profile under a low-protein diet. American Journal of Physiology. Endocrinology and Metabolism 317 (6):E1015–E1021. doi: 10.1152/ajpendo.00022.2019.
   PubMed Web of Science ®Google Scholar
• Chandler, R. J., P. M. Zerfas, S. Shanske, J. Sloan, V. Hoffmann, S. DiMauro, and C. P. Venditti. 2009. Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB Journal 23 (4):1252–1261. doi: 10.1096/fj.08-121848.
   PubMed Web of Science ®Google Scholar
• Chen, Q., and R. A. Reimer. 2009. Dairy protein and leucine alter GLP-1 release and MRNA of genes involved in intestinal lipid metabolism in vitro. Nutrition 25 (3):340–349. doi: 10.1016/j.nut.2008.08.012.
   PubMed Web of Science ®Google Scholar
• Cheng, Q., V. D. Beltran, S. M. H. Chan, J. R. Brown, A. Bevington, and T. P. Herbert. 2016. System-L Amino acid transporters play a key role in pancreatic β-cell signalling and function. Journal of Molecular Endocrinology 56 (3):175–187. doi: 10.1530/JME-15-0212.
   PubMed Web of Science ®Google Scholar
• Cheng, Q., N. Shah, A. Bröer, S. Fairweather, Y. Jiang, D. Schmoll, B. Corry, and S. Bröer. 2017. Identification of novel inhibitors of the amino acid transporter B0 AT1 (SLC6A19), a potential target to induce protein restriction and to treat type 2 diabetes. British Journal of Pharmacology 174 (6):468–482. doi: 10.1111/bph.13711.
   PubMed Web of Science ®Google Scholar
• Cheng, Y., Q. Meng, C. Wang, H. Li, Z. Huang, S. Chen, F. Xiao, and F. Guo. 2010. Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue. Diabetes 59 (1):17–25. doi: 10.2337/db09-0929.
   PubMed Web of Science ®Google Scholar
• Choi, S., B. Disilvio, M. H. Fernstrom, and J. D. Fernstrom. 2013. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines. Amino Acids 45 (5):1133–1142. doi: 10.1007/s00726-013-1566-1.
   PubMed Web of Science ®Google Scholar
• Cifarelli, V., S. C. Beeman, G. I. Smith, J. Yoshino, D. Morozov, J. W. Beals, B. D. Kayser, J. D. Watrous, M. Jain, B. W. Patterson, et al. 2020. Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity. The Journal of Clinical Investigation 130 (12):6688–6699. doi: 10.1172/jci141828.
   PubMed Web of Science ®Google Scholar
• Connelly, M. A., J. Wolak-Dinsmore, and R. P. F. Dullaart. 2017. Branched chain amino acids are associated with insulin resistance independent of leptin and adiponectin in subjects with varying degrees of glucose tolerance. Metabolic Syndrome and Related Disorders 15 (4):183–186. doi: 10.1089/met.2016.0145.
   PubMed Web of Science ®Google Scholar
• Coppola, A., B. R. Wenner, O. Ilkayeva, R. D. Stevens, M. Maggioni, T. A. Slotkin, E. D. Levin, and C. B. Newgard. 2013. Branched-chain amino acids alter neurobehavioral function in rats. American Journal of Physiology. Endocrinology and Metabolism 304 (4):E405–E413. doi: 10.1152/ajpendo.00373.2012.
   PubMed Web of Science ®Google Scholar
• Coqueiro, A. Y., M. M. Rogero, and J. Tirapegui. 2019. Glutamine as an anti-fatigue amino acid in sports nutrition. Nutrients 11 (4):863. doi: 10.3390/nu040863.
   PubMed Web of Science ®Google Scholar
• Cormerais, Y., S. Giuliano, R. LeFloch, B. Front, J. Durivault, E. Tambutté, P.-A. Massard, L. R. de la Ballina, H. Endou, M. F. Wempe, et al. 2016. Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of MTORC1 and tumor growth. Cancer Research 76 (15):4481–4492. doi: 10.1158/0008-5472.CAN-15-3376.
   PubMed Web of Science ®Google Scholar
• Cornu, M., W. Oppliger, V. Albert, A. M. Robitaille, F. Trapani, L. Quagliata, T. Fuhrer, U. Sauer, L. Terracciano, and M. N. Hall. 2014. Hepatic MTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. Proceedings of the National Academy of Sciences of the United States of America 111 (32):11592–11599. doi: 10.1073/pnas.1412047111.
   PubMed Web of Science ®Google Scholar
• Costanzo, M., M. Caterino, A. Cevenini, V. Jung, C. Chhuon, J. Lipecka, R. Fedele, I. C. Guerrera, and M. Ruoppolo. 2020. Proteomics reveals that methylmalonyl-coa mutase modulates cell architecture and increases susceptibility to stress. International Journal of Molecular Sciences 21 (14):4998. doi: 10.3390/ijms21144998.
   PubMed Web of Science ®Google Scholar
• Crossland, H., K. Smith, I. Idris, B. E. Phillips, P. J. Atherton, and D. J. Wilkinson. 2020. Exploring mechanistic links between extracellular BCAA & muscle insulin resistance: An in vitro approach. American Journal of Physiology-Cell Physiology 319 (6):C1151–C1157. doi: 10.1152/ajpcell.00377.2020.
   PubMed Web of Science ®Google Scholar
• Cummings, N. E., E. M. Williams, I. Kasza, E. N. Konon, M. D. Schaid, B. A. Schmidt, C. Poudel, D. S. Sherman, D. Yu, S. I. Arriola Apelo, et al. 2018. Restoration of metabolic health by decreased consumption of branched-chain amino acids. The Journal of Physiology 596 (4):623–645. doi: 10.1113/JP275075.
   PubMed Web of Science ®Google Scholar
• Curtis, J. M., W. S. Hahn, M. D. Stone, J. J. Inda, D. J. Droullard, J. P. Kuzmicic, M. A. Donoghue, E. K. Long, A. G. Armien, S. Lavandero, et al. 2012. Protein carbonylation and adipocyte mitochondrial function. The Journal of Biological Chemistry 287 (39):32967–32980. doi: 10.1074/jbc.M112.400663.
   PubMed Web of Science ®Google Scholar
• D’Antona, G., M. Ragni, A. Cardile, L. Tedesco, M. Dossena, F. Bruttini, F. Caliaro, G. Corsetti, R. Bottinelli, M. O. Carruba, et al. 2010. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metabolism 12 (4):362–372. doi: 10.1016/j.cmet.2010.08.016.
   PubMed Web of Science ®Google Scholar
• Dam, G., P. Ott, N. K. Aagaard, and H. Vilstrup. 2013. Branched-chain amino acids and muscle ammonia detoxification in cirrhosis. Metabolic Brain Disease 28 (2):217–220. doi: 10.1007/s11011-013-9377-3.
   PubMed Web of Science ®Google Scholar
• Danthi, S. J., B. Liang, O. Smicker, B. Coupland, J. Gregory, E. Gefteas, D. Tietz, H. Klodnitsky, K. Randall, A. Belanger, et al. 2019. Identification and characterization of inhibitors of a neutral amino acid transporter, SLC6A19, using two functional cell-based assays. SLAS Discovery 24 (2):111–120. doi: 10.1177/2472555218794627.
   PubMed Web of Science ®Google Scholar
• David, J., D. Dardevet, L. Mosoni, I. Savary-Auzeloux, and S. Polakof. 2019. Impaired skeletal muscle branched-chain amino acids catabolism contributes to their increased circulating levels in a non-obese insulin-resistant fructose-fed rat model. Nutrients 11 (2):355. doi: 10.3390/nu11020355.
   PubMed Web of Science ®Google Scholar
• Del Coco, L., D. Vergara, S. De Matteis, E. Mensà, J. Sabbatinelli, F. Prattichizzo, A. R. Bonfigli, et al. 2019. NMR-based metabolomic approach tracks potential serum biomarkers of disease progression in patients with type 2 diabetes mellitus. Journal of Clinical Medicine 8 (5):720. doi: 10.3390/jcm8050720.
   PubMed Web of Science ®Google Scholar
• Devries, M. C., C. McGlory, D. R. Bolster, A. Kamil, M. Rahn, L. Harkness, S. K. Baker, and S. M. Phillips. 2018. Leucine, not total protein, content of a supplement is the primary determinant of muscle protein anabolic responses in healthy older women. The Journal of Nutrition 148 (7):1088–1095. doi: 10.1093/jn/nxy091.
   PubMed Web of Science ®Google Scholar
• Dewulf, E. M., P. D. Cani, S. P. Claus, S. Fuentes, P. G. B. Puylaert, A. M. Neyrinck, L. B. Bindels, W. M. de Vos, G. R. Gibson, J.-P. Thissen, et al. 2013. Insight into the prebiotic concept: Lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62 (8):1112–1121. doi: 10.1136/gutjnl-2012-303304.
   PubMed Web of Science ®Google Scholar
• Dhanani, Z. N., G. Mann, and O. A. J. Adegoke. 2019. Depletion of branched-chain aminotransferase 2 (BCAT2) enzyme impairs myoblast survival and myotube formation. Physiological Reports 7 (23):e14299. doi: 10.14814/phy2.14299.
   PubMed Web of Science ®Google Scholar
• Dickinson, J. M., C. S. Fry, M. J. Drummond, D. M. Gundermann, D. K. Walker, E. L. Glynn, K. L. Timmerman, S. Dhanani, E. Volpi, and B. B. Rasmussen. 2011. Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids. The Journal of Nutrition 141 (5):856–862. doi: 10.3945/jn.111.139485.
   PubMed Web of Science ®Google Scholar
• Doisaki, M., Y. Katano, I. Nakano, Y. Hirooka, A. Itoh, M. Ishigami, K. Hayashi, H. Goto, Y. Fujita, Y. Kadota, et al. 2010. Regulation of hepatic branched-chain alpha-keto acid dehydrogenase kinase in a rat model for type 2 diabetes mellitus at different stages of the disease. Biochemical and Biophysical Research Communications 393 (2):303–307. doi: 10.1016/j.bbrc.2010.02.004.
   PubMed Web of Science ®Google Scholar
• Drummond, M. J., P. T. Reidy, L. M. Baird, B. K. Dalley, and M. T. Howard. 2017. Leucine differentially regulates gene-specific translation in mouse skeletal muscle. The Journal of Nutrition 147 (9):jn251181. doi: 10.3945/jn.117.251181.
   Web of Science ®Google Scholar
• Du, Y., Q. Meng, Q. Zhang, and F. Guo. 2012. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT. Amino Acids 43 (2):725–734. doi: 10.1007/s00726-011-1123-8.
   PubMed Web of Science ®Google Scholar
• Elshorbagy, A. K., D. Samocha-Bonet, F. Jernerén, C. Turner, H. Refsum, and L. K. Heilbronn. 2018. Food overconsumption in healthy adults triggers early and sustained increases in serum branched-chain amino acids and changes in cysteine linked to fat gain. The Journal of Nutrition 148 (7):1073–1080. doi: 10.1093/jn/nxy062.
   PubMed Web of Science ®Google Scholar
• Engin, A. 2017. Adipose tissue hypoxia in obesity and its impact on preadipocytes and macrophages: Hypoxia hypothesis. Advances in Experimental Medicine and Biology 960:305–326. doi: 10.1007/978-3-319-48382-5_13.
   PubMed Web of Science ®Google Scholar
• Estrada-Alcalde, I., M. R. Tenorio-Guzman, A. R. Tovar, D. Salinas-Rubio, I. Torre-Villalvazo, N. Torres, and L. G. Noriega. 2017. Metabolic fate of branched-chain amino acids during adipogenesis, in adipocytes from obese mice and C2C12 myotubes. Journal of Cellular Biochemistry 118 (4):808–818. doi: 10.1002/jcb.25755.
   PubMed Web of Science ®Google Scholar
• Everman, S., C. Meyer, L. Tran, N. Hoffman, C. C. Carroll, W. L. Dedmon, and C. S. Katsanos. 2016. Insulin does not stimulate muscle protein synthesis during increased plasma branched-chain amino acids alone but still decreases whole body proteolysis in humans. American Journal of Physiology-Endocrinology and Metabolism 311 (4):E671–E677. doi: 10.1152/ajpendo.00120.2016.
   PubMed Web of Science ®Google Scholar
• Falavigna, G., J. Alves de Araújo, M. M. Rogero, I. S. d O. Pires, R. G. Pedrosa, E. Martins, I. Alves de Castro, and J. Tirapegui. 2012. Effects of diets supplemented with branched-chain amino acids on the performance and fatigue mechanisms of rats submitted to prolonged physical exercise. Nutrients 4 (11):1767–1780. doi: 10.3390/nu4111767.
   PubMed Web of Science ®Google Scholar
• Feng, B., C. Banner, and S. R. Max. 1990. Effect of diabetes on glutamine synthetase expression in rat skeletal muscles. American Journal of Physiology - Endocrinology and Metabolism 258 (5 Pt 1):E762–E766. doi: 10.1152/ajpendo.1990.258.5.e762.
   Google Scholar
• Feng, X., A. Sureda, S. Jafari, Z. Memariani, D. Tewari, G. Annunziata, L. Barrea, S. T. S. Hassan, K. Šmejkal, M. Malaník, et al. 2019. Berberine in cardiovascular and metabolic diseases: From mechanisms to therapeutics. Theranostics 9 (7):1923–1951. doi: 10.7150/thno.30787.
   PubMed Web of Science ®Google Scholar
• Ferriero, R., and N. Brunetti-Pierri. 2013. Phenylbutyrate increases activity of pyruvate dehydrogenase complex. Oncotarget 4 (6):804–805. doi: 10.18632/oncotarget.1000.
   PubMedGoogle Scholar
• Festa, A., K. Williams, R. P. Tracy, L. E. Wagenknecht, and S. M. Haffner. 2006. Progression of plasminogen activator inhibitor-1 and fibrinogen levels in relation to incident type 2 diabetes. Circulation 113 (14):1753–1759. doi: 10.1161/CIRCULATIONAHA.106.616177.
   PubMed Web of Science ®Google Scholar
• Fiehn, O., W. T. Garvey, J. W. Newman, K. H. Lok, C. L. Hoppel, and S. H. Adams. 2010. Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS One 5 (12):e15234. doi: 10.1371/journal.pone.0015234.
   PubMed Web of Science ®Google Scholar
• Fontana, L., N. E. Cummings, S. I. Arriola Apelo, J. C. Neuman, I. Kasza, B. A. Schmidt, E. Cava, F. Spelta, V. Tosti, F. A. Syed, et al. 2016. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Reports 16 (2):520–530. doi: 10.1016/j.celrep.2016.05.092.
   PubMed Web of Science ®Google Scholar
• Foster, D. W. 2012. Malonyl-CoA: The regulator of fatty acid synthesis and oxidation. Journal of Clinical Investigation 122 (6):1958–1959. doi: 10.1172/JCI63967.
   PubMed Web of Science ®Google Scholar
• Fouré, A., and D. Bendahan. 2017. Is branched-chain amino acids supplementation an efficient nutritional strategy to alleviate skeletal muscle damage? A systematic review. Nutrients 9 (10):1047. doi: 10.3390/nu9101047.
   PubMed Web of Science ®Google Scholar
• Freudenberg, A., K. J. Petzke, and S. Klaus. 2013. Dietary L-leucine and L-alanine supplementation have similar acute effects in the prevention of high-fat diet-induced obesity. Amino Acids 44 (2):519–528. doi: 10.1007/s00726-012-1363-2.
   PubMed Web of Science ®Google Scholar
• Fryburg, D. A., E. J. Barrett, R. J. Louard, and R. A. Gelfand. 1990. Effect of starvation on human muscle protein metabolism and its response to insulin. The American Journal of Physiology 259 (4 Pt 1):E477–E482. doi: 10.1152/ajpendo.1990.259.4.e477.
   PubMedGoogle Scholar
• Fu, L., A. Bruckbauer, F. Li, Q. Cao, X. Cui, R. Wu, H. Shi, M. B. Zemel, and B. Xue. 2015. Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice. Metabolism 64 (7):845–856. doi: 10.1016/j.metabol.2015.03.007.
   PubMed Web of Science ®Google Scholar
• Fu, W., and M. N. Hall. 2020. Regulation of MTORC2 signaling. Genes 11 (9):1045. doi: 10.3390/genes11091045.
   PubMed Web of Science ®Google Scholar
• Gannaban, R. B., C. NamKoong, H. H. Ruiz, H. J. Choi, and A. C. Shin. 2021. Central regulation of branched-chain amino acids is mediated by AgRP neurons. Diabetes 70 (1):62–75. doi: 10.2337/db20-0510.
   PubMed Web of Science ®Google Scholar
• Gawedzka, A., M. Grandys, K. Duda, J. Zapart-Bukowska, J. A. Zoladz, and J. Majerczak. 2020. Plasma BCAA concentrations during exercise of varied intensities in young healthy men-the impact of endurance training. PeerJ 8 (December):e10491. doi: 10.7717/peerj.10491.
   PubMedGoogle Scholar
• Ghoraba, D. A., M. M. Mohammed, and O. K. Zaki. 2015. Mutation analysis of methylmalonyl CoA mutase gene exon 2 in Egyptian families: Identification of 25 novel allelic variants. Meta Gene 3 (February):71–88. doi: 10.1016/j.mgene.2014.02.001.
   PubMedGoogle Scholar
• Gibson, R., Y. Zhao, J. Jaskiewicz, S. E. Fineberg, and R. A. Harris. 1993. Effects of diabetes on the activity and content of the branched-chain alpha-ketoacid dehydrogenase complex in liver. Archives of Biochemistry and Biophysics 306 (1):22–28. doi: 10.1006/abbi.1993.1475.
   PubMed Web of Science ®Google Scholar
• Gluud, L. L., G. Dam, M. Borre, I. Les, J. Cordoba, G. Marchesini, N. K. Aagaard, and H. Vilstrup. 2013. Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: What is the evidence?Metabolic Brain Disease 28 (2):221–225. doi: 10.1007/s11011-012-9372-0.
   PubMed Web of Science ®Google Scholar
• Gluud, L. L., G. Dam, I. Les, G. Marchesini, M. Borre, N. K. Aagaard, and H. Vilstrup. 2017. Branched-chain amino acids for people with hepatic encephalopathy. The Cochrane Database of Systematic Reviews 5:CD001939. doi: 10.1002/14651858.CD001939.pub4.
   PubMedGoogle Scholar
• Goldberg, E. J., K. A. Buddo, K. L. McLaughlin, R. F. Fernandez, A. S. Pereyra, C. E. Psaltis, C.-T. Lin, J. T. Hagen, I. N. Boykov, T. K. Nguyen, et al. 2019. Tissue-specific characterization of mitochondrial branched-chain keto acid oxidation using a multiplexed assay platform. The Biochemical Journal 476 (10):1521–1537. doi: 10.1042/BCJ20190182.
   PubMedGoogle Scholar
• Gray, S., B. Wang, Y. Orihuela, E.-G. Hong, S. Fisch, S. Haldar, G. W. Cline, J. K. Kim, O. D. Peroni, B. B. Kahn, et al. 2007. Regulation of gluconeogenesis by Krüppel-like factor 15. Cell Metabolism 5 (4):305–312. doi: 10.1016/j.cmet.2007.03.002.
   PubMed Web of Science ®Google Scholar
• Green, C. R., M. Wallace, A. S. Divakaruni, S. A. Phillips, A. N. Murphy, T. P. Ciaraldi, and C. M. Metallo. 2016. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nature Chemical Biology 12 (1):15–21. doi: 10.1038/nchembio.1961.
   PubMed Web of Science ®Google Scholar
• Grimsrud, P. A., M. J. Picklo, T. J. Griffin, and D. A. Bernlohr. 2007. Carbonylation of adipose proteins in obesity and insulin resistance: Identification of adipocyte fatty acid-binding protein as a cellular target of 4-hydroxynonenal. Molecular & Cellular Proteomics 6 (4):624–637. doi: 10.1074/mcp.M600120-MCP200.
   PubMed Web of Science ®Google Scholar
• Guo, F., and D. R. Cavener. 2007. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metabolism 5 (2):103–114. doi: 10.1016/j.cmet.2007.01.001.
   PubMed Web of Science ®Google Scholar
• Halford, J. C. G., J. A. Harrold, E. J. Boyland, C. L. Lawton, and J. E. Blundell. 2007. Serotonergic drugs: Effects on appetite expression and use for the treatment of obesity. Drugs 67 (1):27–55. doi: 10.2165/00003495-200767010-00004.
   PubMed Web of Science ®Google Scholar
• Han, J. L., and H. L. Lin. 2014. Intestinal microbiota and type 2 diabetes: From mechanism insights to therapeutic perspective. World Journal of Gastroenterology 20 (47):17737–17745. doi: 10.3748/wjg.v20.i47.17737.
   PubMed Web of Science ®Google Scholar
• Harris, L., L. S. Ann, G. I. Smith, B. W. Patterson, R. S. Ramaswamy, A. L. Okunade, S. C. Kelly, L. C. Porter, S. Klein, J. Yoshino, et al. 2017. Alterations in 3-hydroxyisobutyrate and FGF21 metabolism are associated with protein ingestion-induced insulin resistance. Diabetes 66 (7):1871–1878. doi: 10.2337/db16-1475.
   PubMed Web of Science ®Google Scholar
• Harris, R. A., R. Kobayashi, T. Murakami, and Y. Shimomura. 2001. Regulation of branched-Chain alpha-keto acid dehydrogenase kinase expression in rat liver. The Journal of Nutrition 131 (3):841S–845S. doi: 10.1093/jn/131.3.841S.
   PubMed Web of Science ®Google Scholar
• Hayase, S., K. Kumamoto, K. Saito, Y. Kofunato, Y. Sato, H. Okayama, K. Miyamoto, S. Ohki, and S. Takenoshita. 2017. L-type amino acid transporter 1 expression is upregulated and associated with cellular proliferation in colorectal cancer. Oncology Letters 14 (6):7410–7416. doi: 10.3892/ol.2017.7148.
   PubMed Web of Science ®Google Scholar
• Herman, M. A., P. She, O. D. Peroni, C. J. Lynch, and B. B. Kahn. 2010. Adipose tissue branched chain amino acid (BCAA) ­metabolism modulates circulating BCAA levels. The Journal of Biological Chemistry 285 (15):11348–11356. doi: 10.1074/jbc.M109.075184.
   PubMed Web of Science ®Google Scholar
• Hernández-Alvarez, M. I., A. Díaz-Ramos, M. Berdasco, J. Cobb, E. Planet, D. Cooper, A. Pazderska, K. Wanic, D. O’Hanlon, A. Gomez, et al. 2017. Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism. Scientific Reports 7 (1):13850. doi: 10.1038/s41598-017-14120-6.
   PubMedGoogle Scholar
• Hewton, K. G., A. S. Johal, and S. J. Parker. 2021. Transporters at the interface between cytosolic and mitochondrial amino acid metabolism. Metabolites 11(2):112. doi: 10.3390/metabo11020112.
   PubMed Web of Science ®Google Scholar
• Higuchi, N., M. Kato, M. Miyazaki, M. Tanaka, M. Kohjima, T. Ito, M. Nakamuta, M. Enjoji, K. Kotoh, and R. Takayanagi. 2011. Potential role of branched-chain amino acids in glucose metabolism through the accelerated induction of the glucose-sensing apparatus in the liver. Journal of Cellular Biochemistry 112 (1):30–38. doi: 10.1002/jcb.22688.
   PubMed Web of Science ®Google Scholar
• Holecek, M. 2013. Branched-chain amino acids and ammonia metabolism in liver disease: Therapeutic implications. Nutrition 29 (10):1186–1191. doi: 10.1016/j.nut.2013.01.022.
   PubMed Web of Science ®Google Scholar
• Holeček, M. 2018. Branched-chain amino acids in health and disease: Metabolism, alterations in blood plasma, and as supplements. Nutrition & Metabolism 15 (1):33. doi: 10.1186/s12986-018-0271-1.
   PubMedGoogle Scholar
• Holeček, M. 2020. Why are branched-chain amino acids increased in starvation and diabetes?Nutrients 12 (10):3087. doi: 10.3390/nu12103087.
   PubMed Web of Science ®Google Scholar
• Holecek, M., R. Kandar, L. Sispera, and M. Kovarik. 2011. Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: Different sensitivity of red and white muscle. Amino Acids 40 (2):575–584. doi: 10.1007/s00726-010-0679-z.
   PubMed Web of Science ®Google Scholar
• Horiuchi, M., T. Takeda, H. Takanashi, Y. Ozaki-Masuzawa, Y. Taguchi, Y. Toyoshima, L. Otani, H. Kato, M. Sone-Yonezawa, F. Hakuno, et al. 2017. Branched-chain amino acid supplementation restores reduced insulinotropic activity of a low-protein diet through the vagus nerve in rats. Nutrition & Metabolism 14 (1):59. doi: 10.1186/s12986-017-0215-1.
   PubMedGoogle Scholar
• Howard, J. K., and J. S. Flier. 2006. Attenuation of leptin and insulin signaling by SOCS proteins. Trends in Endocrinology and Metabolism 17 (9):365–371. doi: 10.1016/j.tem.2006.09.007.
   PubMed Web of Science ®Google Scholar
• Howell, J. J., K. Hellberg, M. Turner, G. Talbott, M. J. Kolar, D. S. Ross, G. Hoxhaj, A. Saghatelian, R. J. Shaw, and B. D. Manning. 2017. Metformin inhibits hepatic MTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metabolism 25 (2):463–471. doi: 10.1016/j.cmet.2016.12.009.
   PubMed Web of Science ®Google Scholar
• Hsiao, G., J. Chapman, J. M. Ofrecio, J. Wilkes, J. L. Resnik, D. Thapar, S. Subramaniam, and D. D. Sears. 2011. Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats. American Journal of Physiology. Endocrinology and Metabolism 300 (1):E164–E174. doi: 10.1152/ajpendo.00219.2010.
   PubMed Web of Science ®Google Scholar
• Hu, H., L. Li, C. Wang, H. He, K. Mao, X. Ma, R. Shi, Y. Oh, FWei Zhang, Y. Lu, et al. 2014. 4-Phenylbutyric acid increases GLUT4 gene expression through suppression of HDAC5 but not endoplasmic reticulum stress. Cellular Physiology and Biochemistry 33 (6):1899–1910. doi: 10.1159/000362967.
   PubMedGoogle Scholar
• Iannitti, T., and B. Palmieri. 2011. Clinical and experimental applications of sodium phenylbutyrate. Drugs in R&D 11 (3):227–249. doi: 10.2165/11591280-000000000-00000.
   PubMedGoogle Scholar
• Isanejad, M., A. Z. LaCroix, C. A. Thomson, L. Tinker, J. C. Larson, Q. Qi, L. Qi, R. M. Cooper-DeHoff, L. S. Phillips, R. L. Prentice, et al. 2017. Branched-chain amino acid, meat intake and risk of type 2 diabetes in the women’s health initiative. The British Journal of Nutrition 117 (11):1523–30. doi: 10.1017/S0007114517001568.
   PubMed Web of Science ®Google Scholar
• Ishikawa, T., Y. Kitaura, Y. Kadota, Y. Morishita, M. Ota, F. Yamanaka, M. Xu, M. Ikawa, N. Inoue, F. Kawano, et al. 2017. Muscle-specific deletion of BDK amplifies loss of myofibrillar protein during protein undernutrition. Scientific Reports 7 (1):39825. doi: 10.1038/srep39825.
   PubMedGoogle Scholar
• Iwasa, M., T. Ishihara, R. Mifuji-Moroka, N. Fujita, Y. Kobayashi, H. Hasegawa, K. Iwata, M. Kaito, and Y. Takei. 2015. Elevation of branched-chain amino acid levels in diabetes and NAFL and changes with antidiabetic drug treatment. Obesity Research & Clinical Practice 9 (3):293–7. doi: 10.1016/j.orcp.2015.01.003.
   PubMed Web of Science ®Google Scholar
• Jackman, S. R., O. C. Witard, A. Philp, G. A. Wallis, K. Baar, and K. D. Tipton. 2017. Branched-chain amino acid ingestion stimulates muscle myofibrillar protein synthesis following resistance exercise in humans. Frontiers in Physiology 8 (JUN):390. doi: 10.3389/fphys.2017.00390.
   PubMedGoogle Scholar
• Jang, C., S. F. Oh, S. Wada, G. C. Rowe, L. Liu, M. C. Chan, J. Rhee, A. Hoshino, B. Kim, A. Ibrahim, et al. 2016. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nature Medicine 22 (4):421–6. doi: 10.1038/nm.4057.
   PubMed Web of Science ®Google Scholar
• Javed, K., and S. J. Fairweather. 2019. Amino acid transporters in the regulation of insulin secretion and signalling. Biochemical Society Transactions 47 (2):571–90. doi: 10.1042/BST20180250.
   PubMedGoogle Scholar
• Jennings, A., A. MacGregor, T. Pallister, T. Spector, and A. Cassidy. 2016. Associations between branched chain amino acid intake and biomarkers of adiposity and cardiometabolic health independent of genetic factors: A twin study. International Journal of Cardiology 223 (November):992–8. doi: 10.1016/j.ijcard.2016.08.307.
   PubMedGoogle Scholar
• Jhanwar-Uniyal, M., J. V. Wainwright, A. L. Mohan, M. E. Tobias, R. Murali, C. D. Gandhi, and M. H. Schmidt. 2019. Diverse signaling mechanisms of MTOR complexes: MTORC1 and MTORC2 in forming a formidable relationship. Advances in Biological Regulation 72 (May):51–62. doi: 10.1016/j.jbior.2019.03.003.
   PubMedGoogle Scholar
• Jiang, Y., A. J. Rose, T. P. Sijmonsma, A. Bröer, A. Pfenninger, S. Herzig, D. Schmoll, and S. Bröer. 2015. Mice lacking neutral amino acid transporter B(0)AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control. Molecular Metabolism 4 (5):406–17. doi: 10.1016/j.molmet.2015.02.003.
   PubMed Web of Science ®Google Scholar
• Jiao, J., S.-F. Han, W. Zhang, J.-Y. Xu, X. Tong, X.-B. Yin, L.-X. Yuan, and L.-Q. Qin. 2016. Chronic leucine supplementation improves lipid metabolism in C57BL/6J mice fed with a high-fat/cholesterol diet. Food & Nutrition Research 60 (September):31304. doi: 10.3402/fnr.v60.31304.
   PubMedGoogle Scholar
• Jung, T. W., H.-J. Hwang, H. C. Hong, H. J. Yoo, S. H. Baik, and K. M. Choi. 2015. BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK-PPARδ-dependent pathway in mice. Diabetologia 58 (9):2096–105. doi: 10.1007/s00125-015-3663-z.
   PubMed Web of Science ®Google Scholar
• Jung, T. W., H. S. Park, G. H. Choi, D. Kim, and T. Lee. 2018. β-aminoisobutyric acid attenuates LPS-induced inflammation and insulin resistance in adipocytes through AMPK-mediated pathway. Journal of Biomedical Science 25 (1):27. doi: 10.1186/s12929-018-0431-7.
   PubMedGoogle Scholar
• Kadota, Y., S. Kazama, G. Bajotto, Y. Kitaura, and Y. Shimomura. 2012. Clofibrate-induced reduction of plasma branched-chain amino acid concentrations impairs glucose tolerance in rats. JPEN. Journal of Parenteral and Enteral Nutrition 36 (3):337–43. doi: 10.1177/0148607111414578.
   PubMed Web of Science ®Google Scholar
• Kadota, Y., T. Toyoda, Y. Kitaura, S. H. Adams, and Y. Shimomura. 2013. Regulation of hepatic branched-chain α-ketoacid dehydrogenase complex in rats fed a high-fat diet. Obesity Research & Clinical Practice 7 (6):e439–e444. doi: 10.1016/j.orcp.2013.07.003.
   PubMed Web of Science ®Google Scholar
• Kainulainen, H., J. J. Hulmi, and U. M. Kujala. 2013. Potential role of branched-chain amino acid catabolism in regulating fat oxidation. Exercise and Sport Sciences Reviews 41 (4):194–200. doi: 10.1097/JES.0b013e3182a4e6b6.
   PubMed Web of Science ®Google Scholar
• Kalavalapalli, S., F. Bril, J. P. Koelmel, K. Abdo, J. Guingab, P. Andrews, W.-Y. Li, D. Jose, R. A. Yost, R. F. Frye, et al. 2018. Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis. American Journal of Physiology. Endocrinology and Metabolism 315 (2):E163–E173. doi: 10.1152/ajpendo.00023.2018.
   PubMed Web of Science ®Google Scholar
• Kamei, Y., Y. Hatazawa, R. Uchitomi, R. Yoshimura, and S. Miura. 2020. Regulation of skeletal muscle function by amino acids. Nutrients 12 (1):261. doi: 10.3390/nu12010261.
   PubMed Web of Science ®Google Scholar
• Kang, S., E. R. Chemaly, R. J. Hajjar, and D. Lebeche. 2011. Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/MTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. The Journal of Biological Chemistry 286 (21):18465–73. doi: 10.1074/jbc.M110.200022.
   PubMed Web of Science ®Google Scholar
• Kappel, B. A., M. Lehrke, K. Schütt, A. Artati, J. Adamski, C. Lebherz, and N. Marx. 2017. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation 136 (10):969–72. doi: 10.1161/CIRCULATIONAHA.117.029166.
   PubMed Web of Science ®Google Scholar
• Karakas, S. E., B. Perroud, T. Kind, M. Palazoglu, and O. Fiehn. 2016. Changes in plasma metabolites and glucose homeostasis during omega-3 polyunsaturated fatty acid supplementation in women with polycystic ovary syndrome. BBA Clinical 5:179–85. doi: 10.1016/j.bbacli.2016.04.003.
   PubMedGoogle Scholar
• Karusheva, Y., T. Koessler, K. Strassburger, D. Markgraf, L. Mastrototaro, T. Jelenik, M.-C. Simon, D. Pesta, O.-P. Zaharia, K. Bódis, et al. 2019. Short-term dietary reduction of branched-chain amino acids reduces meal-induced insulin secretion and modifies microbiome composition in type 2 diabetes: A randomized controlled crossover trial. The American Journal of Clinical Nutrition 110 (5):1098–107. doi: 10.1093/ajcn/nqz191.
   PubMed Web of Science ®Google Scholar
• Karusheva, Y., K. Strassburger, D. F. Markgraf, O.-P. Zaharia, K. Bódis, T. Kössler, A. Tura, G. Pacini, V. Burkart, M. Roden, et al. 2021. Branched-chain amino acids associate negatively with postprandial insulin secretion in recent-onset diabetes. Journal of the Endocrine Society 5 (6):1–9. doi: 10.1210/jendso/bvab067.
   Web of Science ®Google Scholar
• Karwi, Q., G. Mezbah Uddin, C. S. Wagg, and G. D. Lopaschuk. 2020. Branched-chain keto acids, not branched-chain amino acids, impairs cardiac insulin sensitivity by disrupting insulin signaling in the mitochondria. Circulation Research 127 (Suppl_1):AMP125. doi: 10.1161/res.127.suppl_1.MP125.
   Google Scholar
• Katagiri, R., A. Goto, S. Budhathoki, T. Yamaji, H. Yamamoto, Y. Kato, M. Iwasaki, and S. Tsugane. 2018. Association between plasma concentrations of branched-chain amino acids and adipokines in Japanese adults without diabetes. Scientific Reports 8 (1):1043–8. doi: 10.1038/s41598-018-19388-w.
   PubMedGoogle Scholar
• Kawaguchi, T., Y. Nagao, H. Matsuoka, T. Ide, and M. Sata. 2008. Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. International Journal of Molecular Medicine 22 (1):105–12. doi: 10.3892/ijmm.22.1.105.
   PubMed Web of Science ®Google Scholar
• Kephart, W. C., T. D. Wachs, R. M. Thompson, C. B. Mobley, C. D. Fox, J. R. McDonald, B. S. Ferguson, K. C. Young, B. Nie, J. S. Martin, et al. 2015. Ten weeks of branched chain amino acid supplementation improves select performance and immunological variables in trained cyclists. Journal of the International Society of Sports Nutrition 12 (S1):P20. doi: 10.1186/1550-2783-12-S1-P20.
   PubMedGoogle Scholar
• Khan, S., S. K. Komarya, and G. Jena. 2017. Phenylbutyrate and β-cell function: Contribution of histone deacetylases and ER stress inhibition. Epigenomics 9 (5):711–20. doi: 10.2217/epi-2016-0160.
   PubMed Web of Science ®Google Scholar
• Kitsy, A., S. Carney, J. C. Vivar, M. S. Knight, M. A. Pointer, J. K. Gwathmey, and S. Ghosh. 2014. Effects of leucine supplementation and serum withdrawal on branched-chain amino acid pathway gene and protein expression in mouse adipocytes. PLoS One 9 (7):e102615. doi: 10.1371/journal.pone.0102615.
   PubMed Web of Science ®Google Scholar
• Knebel, B., K. Strassburger, J. Szendroedi, J. Kotzka, M. Scheer, B. Nowotny, K. Müssig, S. Lehr, G. Pacini, H. Finner, et al. 2016. Specific metabolic profiles and their relationship to insulin resistance in recent-onset type 1 and type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism 101 (5):2130–40. doi: 10.1210/jc.2015-4133.
   PubMed Web of Science ®Google Scholar
• Kobayashi, R., T. Murakami, M. Obayashi, N. Nakai, J. Jaskiewicz, Y. Fujiwara, Y. Shimomura, and R. A. Harris. 2002. Clofibric acid stimulates branched-chain amino acid catabolism by three mechanisms. Archives of Biochemistry and Biophysics 407 (2):231–40. doi: 10.1016/S0003-9861(02)00472-1.
   PubMed Web of Science ®Google Scholar
• Kondo, H., Y. Minegishi, Y. Komine, T. Mori, I. Matsumoto, K. Abe, I. Tokimitsu, T. Hase, and T. Murase. 2006. Differential regulation of intestinal lipid metabolism-related genes in obesity-resistant A/J vs. obesity-prone C57BL/6J mice. American Journal of Physiology. Endocrinology and Metabolism 291 (5):E1092–E1099. doi: 10.1152/ajpendo.00583.2005.
   PubMed Web of Science ®Google Scholar
• Kovatcheva-Datchary, P., A. Nilsson, R. Akrami, Y. S. Lee, F. De Vadder, T. Arora, A. Hallen, E. Martens, I. Björck, and F. Bäckhed. 2015. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of prevotella. Cell Metabolism 22 (6):971–82. doi: 10.1016/j.cmet.2015.10.001.
   PubMed Web of Science ®Google Scholar
• Koves, T. R., J. R. Ussher, R. C. Noland, D. Slentz, M. Mosedale, O. Ilkayeva, J. Bain, R. Stevens, J. R. B. Dyck, C. B. Newgard, et al. 2008. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metabolism 7 (1):45–56. doi: 10.1016/j.cmet.2007.10.013.
   PubMed Web of Science ®Google Scholar
• Krebs, M., M. Krssak, E. Bernroider, C. Anderwald, A. Brehm, M. Meyerspeer, P. Nowotny, E. Roth, W. Waldhausl, and M. Roden. 2002. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes 51 (3):599–605. doi: 10.2337/diabetes.51.3.599.
   PubMed Web of Science ®Google Scholar
• Kujala, U. M., M. Peltonen, M. K. Laine, J. Kaprio, O. J. Heinonen, J. Sundvall, J. G. Eriksson, A. Jula, S. Sarna, and H. Kainulainen. 2016. Branched-chain amino acid levels are related with surrogates of disturbed lipid metabolism among older men. Frontiers in Medicine 3:57. doi: 10.3389/fmed.2016.00057.
   Web of Science ®Google Scholar
• Lackey, D. E., C. J. Lynch, K. C. Olson, R. Mostaedi, M. Ali, W. H. Smith, F. Karpe, S. Humphreys, D. H. Bedinger, T. N. Dunn, et al. 2013. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. American Journal of Physiology. Endocrinology and Metabolism 304 (11):E1175–E1187. doi: 10.1152/ajpendo.00630.2012.
   PubMed Web of Science ®Google Scholar
• Laeger, T., S. D. Reed, T. M. Henagan, D. H. Fernandez, M. Taghavi, A. Addington, H. Münzberg, R. J. Martin, S. M. Hutson, and C. D. Morrison. 2014. Leucine acts in the brain to suppress food intake but does not function as a physiological signal of low dietary protein. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 307 (3):R310–R320. doi: 10.1152/ajpregu.00116.2014.
   PubMed Web of Science ®Google Scholar
• Laferrère, B., D. Reilly, S. Arias, N. Swerdlow, P. Gorroochurn, B. Bawa, M. Bose, J. Teixeira, R. D. Stevens, B. R. Wenner, et al. 2011. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Science Translational Medicine 3 (80):80re2. doi: 10.1126/scitranslmed.3002043.
   PubMed Web of Science ®Google Scholar
• Lee, C. C., Watkins, S. M. C. Lorenzo, L. E. Wagenknecht, D. Il’Yasova, Yii, D. I. Chen, S. M. Haffner, and A. J. Hanley. 2016. Branched-chain amino acids and insulin metabolism: The insulin resistance atherosclerosis study (IRAS). Diabetes Care 39 (4):582–8. doi: 10.2337/dc15-2284.
   PubMed Web of Science ®Google Scholar
• Lee, J., A. Vijayakumar, P. J. White, Y. Xu, O. Ilkayeva, C. J. Lynch, C. B. Newgard, and B. B. Kahn. 2021. BCAA supplementation in mice with diet-induced obesity alters the metabolome without impairing glucose homeostasis. Endocrinology 162 (7):bqab062. doi: 10.1210/endocr/bqab062.
   PubMed Web of Science ®Google Scholar
• Lee, J. H., Y.-R. Cho, J. H. Kim, J. Kim, H. Y. Nam, S. W. Kim, and J. Son. 2019. Branched-chain amino acids sustain pancreatic cancer growth by regulating lipid metabolism. Experimental & Molecular Medicine 51 (11):1–11. doi: 10.1038/s12276-019-0350-z.
   Google Scholar
• Lerin, C., A. B. Goldfine, T. Boes, M. Liu, S. Kasif, J. M. Dreyfuss, A. L. De Sousa-Coelho, G. Daher, I. Manoli, J. R. Sysol, et al. 2016. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Molecular Metabolism 5 (10):926–36. doi: 10.1016/j.molmet.2016.08.001.
   PubMed Web of Science ®Google Scholar
• Li, D., S. Li, Q. Pan, H. Zhai, M. Peng, X. Wang, and G. Xu. 2018. Gastric mammalian target of rapamycin signaling contributes to inhibition of ghrelin expression induced by Roux-En-Y gastric bypass. Cellular Physiology and Biochemistry 51 (2):664–80. doi: 10.1159/000495325.
   PubMedGoogle Scholar
• Li, T., Z. Zhang, S. C. Kolwicz, L. Abell, N. D. Roe, M. Kim, B. Zhou, Y. Cao, J. Ritterhoff, H. Gu, et al. 2017. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metabolism 25 (2):374–85. doi: 10.1016/j.cmet.2016.11.005.
   PubMed Web of Science ®Google Scholar
• Li, X., X. Wang, R. Liu, Y. Ma, H. Guo, L. Hao, P. Yao, L. Liu, X. Sun, K. He, et al. 2013. Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high-fat diet likely by promoting insulin signaling in insulin-target tissues. Molecular Nutrition & Food Research 57 (6):1067–79. doi: 10.1002/mnfr.201200311.
   PubMed Web of Science ®Google Scholar
• Li, Y., Wang, B. J. Shen, M. Bai, E. Xu. 2020. Berberine attenuates fructose-induced insulin resistance by stimulating the hepatic LKB1/AMPK/PGC-1α pathway in mice. Pharmaceutical Biology 58 (1):385–92. doi: 10.1080/13880209.2020.1756349.
   PubMed Web of Science ®Google Scholar
• Li, Y., Z. Xiong, W. Yan, E. Gao, H. Cheng, G. Wu, Y. Liu, L. Zhang, C. Li, S. Wang, et al. 2020. Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation. Theranostics 10 (12):5623–40. doi: 10.7150/thno.44836.
   PubMed Web of Science ®Google Scholar
• Lian, K., C. Du, Y. Liu, D. Zhu, W. Yan, H. Zhang, Z. Hong, P. Liu, L. Zhang, H. Pei, et al. 2015. Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice. Diabetes 64 (1):49–59. doi: 10.2337/db14-0312.
   PubMed Web of Science ®Google Scholar
• Liao, X., B. Liu, H. Qu, L. Zhang, Y. Lu, Y. Xu, Z. Lyu, and H. Zheng. 2019. A high level of circulating valine is a biomarker for type 2 diabetes and associated with the hypoglycemic effect of sitagliptin. Mediators of Inflammation 2019:1–7. doi: 10.1155/2019/824019.
   Web of Science ®Google Scholar
• Lin, H. V., A. Frassetto, E. J. Kowalik, A. R. Nawrocki, M. M. Lu, J. R. Kosinski, J. A. Hubert, D. Szeto, X. Yao, G. Forrest, et al. 2012. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One 7 (4):e35240. doi: 10.1371/journal.pone.0035240.
   PubMed Web of Science ®Google Scholar
• Liu, H., R. Liu, Y. Xiong, X. Li, X. Wang, Y. Ma, H. Guo, L. Hao, P. Yao, L. Liu, et al. 2014. Leucine facilitates the insulin-stimulated glucose uptake and insulin signaling in skeletal muscle cells: Involving MTORC1 and MTORC2. Amino Acids 46 (8):1971–9. doi: 10.1007/s00726-014-1752-9.
   PubMed Web of Science ®Google Scholar
• Liu, R., H. Li, W. Fan, Q. Jin, T. Chao, Y. Wu, J. Huang, L. Hao, and X. Yang. 2017. Leucine supplementation differently modulates branched-chain amino acid catabolism, mitochondrial function and metabolic profiles at the different stage of insulin resistance in rats on high-fat diet. Nutrients 9 (6):565. doi: 10.3390/nu9060565.
   PubMed Web of Science ®Google Scholar
• Liu, Y., W. Dong, J. Shao, Y. Wang, M. Zhou, and H. Sun. 2017. Branched-chain amino acid negatively regulates KLF15 expression via PI3K-AKT pathway. Frontiers in Physiology 8 (OCT):853. doi: 10.3389/fphys.2017.00853.
   PubMedGoogle Scholar
• Liu, Y., Y. Wang, Y. Ni, C. K. Y. Cheung, K. S. L. Lam, Y. Wang, Z. Xia, D. Ye, J. Guo, M. A. Tse, et al. 2020. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention. Cell Metabolism 31 (1):77–91.e5. doi: 10.1016/j.cmet.2019.11.001.
   PubMed Web of Science ®Google Scholar
• Long, J., Z. Yang, L. Wang, Y. Han, C. Peng, C. Yan, and D. Yan. 2020. Metabolite biomarkers of type 2 diabetes mellitus and pre-diabetes: A systematic review and meta-analysis. BMC Endocrine Disorders 20 (1):174. doi: 10.1186/s12902-020-00653-x.
   PubMed Web of Science ®Google Scholar
• Lu, G., H. Sun, P. She, J.-Y. Youn, S. Warburton, P. Ping, T. M. Vondriska, H. Cai, C. J. Lynch, and Y. Wang. 2009. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured d cells. The Journal of Clinical Investigation 119 (6):1678–87. doi: 10.1172/JCI38151.
   PubMed Web of Science ®Google Scholar
• Lynch, C. J., and S. H. Adams. 2014. Branched-chain amino acids in metabolic signalling and insulin resistance. Nature Reviews. Endocrinology 10 (12):723–36. doi: 10.1038/nrendo.2014.171.
   PubMed Web of Science ®Google Scholar
• Lynch, C. J., S. R. Kimball, Y. Xu, A. C. Salzberg, and Y. I. Kawasawa. 2015. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiological Genomics 47 (11):569–80. doi: 10.1152/physiolgenomics.00055.2015.
   PubMed Web of Science ®Google Scholar
• Ma, Q., X. Zhou, L. Hu, J. Chen, J. Zhu, and A. Shan. 2020. Leucine and isoleucine have similar effects on reducing lipid accumulation, improving insulin sensitivity and increasing the browning of WAT in high-fat diet-induced obese mice. Food & Function 11 (3):2279–90. doi: 10.1039/c9fo03084k.
   PubMed Web of Science ®Google Scholar
• Macotela, Y., B. Emanuelli, A. M. Bång, D. O. Espinoza, J. Boucher, K. Beebe, W. Gall, and C. R. Kahn. 2011. Dietary leucine-an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One 6 (6):e21187. doi: 10.1371/journal.pone.0021187.
   PubMed Web of Science ®Google Scholar
• Mahendran, Y., A. Jonsson, C. T. Have, K. H. Allin, D. R. Witte, M. E. Jørgensen, N. Grarup, O. Pedersen, T. O. Kilpeläinen, and T. Hansen. 2017. Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels. Diabetologia 60 (5):873–8. doi: 10.1007/s00125-017-4222-6.
   PubMed Web of Science ®Google Scholar
• Maida, A., J. S. K. Chan, K. A. Sjøberg, A. Zota, D. Schmoll, B. Kiens, S. Herzig, and A. J. Rose. 2017. Repletion of branched chain amino acids reverses MTORC1 signaling but not improved metabolism during dietary protein dilution. Molecular Metabolism 6 (8):873–81. doi: 10.1016/j.molmet.2017.06.009.
   PubMed Web of Science ®Google Scholar
• Maida, A., A. Zota, K. A. Sjøberg, J. Schumacher, T. P. Sijmonsma, A. Pfenninger, M. M. Christensen, T. Gantert, J. Fuhrmeister, U. Rothermel, et al. 2016. A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution. The Journal of Clinical Investigation 126 (9):3263–78. doi: 10.1172/JCI85946.
   PubMed Web of Science ®Google Scholar
• Mangge, H., S. Zelzer, F. Prüller, W. J. Schnedl, D. Weghuber, D. Enko, P. Bergsten, J. Haybaeck, and A. Meinitzer. 2016. Branched-chain amino acids are associated with cardiometabolic risk profiles found already in lean, overweight and obese young. The Journal of Nutritional Biochemistry 32 (June):123–7. doi: 10.1016/j.jnutbio.2016.02.007.
   PubMedGoogle Scholar
• Marafie, S. K., E. M. Al-Shawaf, J. Abubaker, and H. Arefanian. 2019. Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-MTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells. Biological Research 52 (1):44. doi: 10.1186/s40659-019-0253-4.
   PubMed Web of Science ®Google Scholar
• Mardinoglu, A., S. Gogg, L. A. Lotta, A. Stančáková, A. Nerstedt, J. Boren, M. Blüher, E. Ferrannini, C. Langenberg, N. J. Wareham, et al. 2018. Elevated plasma levels of 3-hydroxyisobutyric acid are associated with incident type 2 diabetes. EBioMedicine 27 (January):151–5. doi: 10.1016/j.ebiom.2017.12.008.
   PubMedGoogle Scholar
• Martin, N. R. W., M. C. Turner, R. Farrington, D. J. Player, and M. P. Lewis. 2017. Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro. Journal of Cellular Physiology 232 (10):2788–97. doi: 10.1002/JCP.25960.
   PubMed Web of Science ®Google Scholar
• Master, P. B. Z., and R. C. O. Macedo. 2021. Effects of dietary supplementation in sport and exercise: A review of evidence on milk proteins and amino acids. Critical Reviews in Food Science and Nutrition 61 (7):1225–39. doi: 10.1080/10408398.2020.1756216.
   PubMed Web of Science ®Google Scholar
• Mayers, J. R., M. E. Torrence, L. V. Danai, T. Papagiannakopoulos, S. M. Davidson, M. R. Bauer, A. N. Lau, B. W. Ji, P. D. Dixit, A. M. Hosios, et al. 2016. Tissue of origin dictates branched-chain amino acid metabolism in mutant kras-driven cancers. Science 353 (6304):1161–5. doi: 10.1126/science.aaf5171.
   PubMed Web of Science ®Google Scholar
• McGarrah, R. W., Zhang, G.-F. B. A. Christopher, Y. Deleye, J. M. Walejko, S. Page, O. Ilkayeva, P. J. White, and Christopher, and B. Newgard. 2020. Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of zucker fatty rats. American Journal of Physiology. Endocrinology and Metabolism 318 (2):E216–E223. doi: 10.1152/ajpendo.00334.2019.
   PubMed Web of Science ®Google Scholar
• Miyake, T., M. Abe, S. Furukawa, Y. Tokumoto, K. Toshimitsu, T. Ueda, S. Yamamoto, M. Hirooka, T. Kumagi, Y. Hiasa, et al. 2012. Long-term branched-chain amino acid supplementation improves glucose tolerance in patients with nonalcoholic steatohepatitis-related cirrhosis. Internal Medicine 51 (16):2151–5. doi: 10.2169/internalmedicine.51.7578.
   PubMed Web of Science ®Google Scholar
• Mizusawa, A., A. Watanabe, M. Yamada, R. Kamei, Y. Shimomura, and Y. Kitaura. 2020. BDK deficiency in cerebral cortex neurons causes neurological abnormalities and affects endurance capacity. Nutrients 12 (8):1–10. doi: 10.3390/nu12082267.
   Web of Science ®Google Scholar
• Moberg, M., W. Apró, B. Ekblom, G. Van Hall, H. Christer Holmberg, and E. Blomstrand. 2016. Activation of MTORC1 by leucine is potentiated by branched-chain amino acids and even more so by essential amino acids following resistance exercise. American Journal of Physiology-Cell Physiology 310 (11):C874–C884. doi: 10.1152/ajpcell.00374.2015.
   PubMed Web of Science ®Google Scholar
• Moghei, M., P. Tavajohi-Fini, B. Beatty, and O. A. J. Adegoke. 2016. Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner. American Journal of Physiology-Cell Physiology 311 (3):C518–C527. doi: 10.1152/ajpcell.00062.2016.
   PubMed Web of Science ®Google Scholar
• Molfino, A., M. I. Amabile, T. Ammann, S. Lai, A. Grosso, L. Lionetto, A. Spagnoli, M. Simmaco, M. Monti, A. Laviano, et al. 2019. Longitudinal physical activity change during hemodialysis and its association with body composition and plasma BAIBA levels. Frontiers in Physiology 10:805. doi: 10.3389/fphys.2019.00805.
   PubMed Web of Science ®Google Scholar
• Mu, W.-C., E. VanHoosier, C. M. Elks, and R. W. Grant. 2018. Long-term effects of dietary protein and branched-chain amino acids on metabolism and inflammation in mice. Nutrients 10 (7):918. doi: 10.3390/nu10070918.
   PubMed Web of Science ®Google Scholar
• Nagao, K., and M. Yamakado. 2016. The role of amino acid profiles in diabetes risk assessment. Current Opinion in Clinical Nutrition and Metabolic Care 19 (5):328–35. doi: 10.1097/MCO.0000000000000305.
   PubMed Web of Science ®Google Scholar
• Nakanishi, K., T. Namisaki, T. Mashitani, K. Kaji, K. Ozaki, S. Saikawa, S. Sato, T. Inoue, Y. Sawada, K. Kitagawa, et al. 2019. Late-evening snack with branched-chain amino acid-enriched nutrients does not always inhibit overt diabetes in patients with cirrhosis: A pilot study. Nutrients 11 (9):2140. doi: 10.3390/nu11092140.
   PubMed Web of Science ®Google Scholar
• Napolitano, L., M. Scalise, M. Koyioni, P. Koutentis, M. Catto, I. Eberini, C. Parravicini, L. Palazzolo, L. Pisani, M. Galluccio, et al. 2017. Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole and dithiazine compounds for development of anticancer drugs. Biochemical Pharmacology 143:39–52. doi: 10.1016/j.bcp.2017.07.006.
   PubMed Web of Science ®Google Scholar
• Neinast, M., D. Murashige, and Z. Arany. 2019. Branched chain amino acids. Annual Review of Physiology 81:139–64. doi: 10.1146/annurev-physiol-020518-114455.
   PubMed Web of Science ®Google Scholar
• Neinast, M. D., C. Jang, S. Hui, D. S. Murashige, Q. Chu, R. J. Morscher, X. Li, L. Zhan, E. White, T. G. Anthony, et al. 2019. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metabolism 29 (2):417–29.e4. doi: 10.1016/j.cmet.2018.10.013.
   PubMed Web of Science ®Google Scholar
• Neishabouri, S., Hallaj, S. M. Hutson, and J. Davoodi. 2015. Chronic activation of MTOR complex 1 by branched chain amino acids and organ hypertrophy. Amino Acids 47 (6):1167–82. doi: 10.1007/s00726-015-1944-y.
   PubMed Web of Science ®Google Scholar
• Newgard, C. B., J. An, J. R. Bain, M. J. Muehlbauer, R. D. Stevens, L. F. Lien, A. M. Haqq, S. H. Shah, M. Arlotto, C. A. Slentz, et al. 2009. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metabolism 9 (4):311–26. doi: 10.1016/j.cmet.2009.02.002.
   PubMed Web of Science ®Google Scholar
• Nie, C., He, T. W. Zhang, and G. Zhang, Xi Ma. 2018. Branched chain amino acids: Beyond nutrition metabolism. International Journal of Molecular Sciences 19 (4):954. doi: 10.3390/ijms19040954.
   PubMed Web of Science ®Google Scholar
• Nilsen, M. S., R. Å. Jersin, A. Ulvik, A. Madsen, A. McCann, P.-A. Svensson, M. K. Svensson, B. G. Nedrebø, O. A. Gudbrandsen, G. S. Tell, et al. 2020. 3-hydroxyisobutyrate, a strong marker of insulin resistance in type 2 diabetes and obesity that modulates white and brown adipocyte metabolism. Diabetes 69 (9):1903–16. doi: 10.2337/db19-1174.
   PubMed Web of Science ®Google Scholar
• Novarino, G., P. El-Fishawy, H. Kayserili, N. A. Meguid, E. M. Scott, J. Schroth, J. L. Silhavy, M. Kara, R. O. Khalil, T. Ben-Omran, et al. 2012. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338 (6105):394–7. doi: 10.1126/science.1224631.
   PubMed Web of Science ®Google Scholar
• Oishi, K., and G. A. Diaz. 2014. Glycerol phenylbutyrate for the chronic management of urea cycle disorders. Expert Review of Endocrinology & Metabolism 9 (5):427–34. doi: 10.1586/17446651.2014.945908.
   PubMedGoogle Scholar
• Ooi, D. S. Q., J. Q. R. Ling, S. A. Sadananthan, S. S. Velan, F. Y. Ong, C. M. Khoo, E. S. Tai, C. J. Henry, M. K. S. Leow, E. Y. H. Khoo, et al. 2021. Branched-chain amino acid supplementation does not preserve lean mass or affect metabolic profile in adults with overweight or obesity in a randomized controlled weight loss intervention. The Journal of Nutrition 151 (4):911–20. doi: 10.1093/jn/nxaa414.
   PubMed Web of Science ®Google Scholar
• Overmyer, K. A., C. R. Evans, N. R. Qi, C. E. Minogue, J. J. Carson, C. J. Chermside-Scabbo, L. G. Koch, S. L. Britton, D. J. Pagliarini, J. J. Coon, et al. 2015. Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation. Cell Metabolism 21 (3):468–78. doi: 10.1016/j.cmet.2015.02.007.
   PubMed Web of Science ®Google Scholar
• Oyarzabal, A., M. Martínez-Pardo, B. Merinero, R. Navarrete, L. R. Desviat, M. Ugarte, and P. Rodríguez-Pombo. 2013. A novel regulatory defect in the branched-chain α-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease. Human Mutation 34 (2):355–62. doi: 10.1002/humu.22242.
   PubMed Web of Science ®Google Scholar
• Pajvani, U. B., X. Du, T. P. Combs, A. H. Berg, M. W. Rajala, T. Schulthess, J. Engel, M. Brownlee, and P. E. Scherer. 2003. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. The Journal of Biological Chemistry 278 (11):9073–85. doi: 10.1074/jbc.M207198200.
   PubMed Web of Science ®Google Scholar
• Pakiet, A., M. Wilczynski, O. Rostkowska, J. Korczynska, P. Jabłonska, L. Kaska, M. Proczko-Stepaniak, E. Sobczak, P. Stepnowski, F. Magkos, et al. 2020. The effect of one anastomosis gastric bypass on branched-chain fatty acid and branched-chain amino acid metabolism in subjects with morbid obesity. Obesity Surgery 30 (1):304–12. doi: 10.1007/s11695-019-04157-z.
   PubMed Web of Science ®Google Scholar
• Pedersen, H. K., V. Gudmundsdottir, H. B. Nielsen, T. Hyotylainen, T. Nielsen, B. A. H. Jensen, K. Forslund, F. Hildebrand, E. Prifti, G. Falony, et al. 2016. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535 (7612):376–81. doi: 10.1038/nature18646.
   PubMed Web of Science ®Google Scholar
• Peyrollier, K., E. Hajduch, A. S. Blair, R. Hyde, and H. S. Hundal. 2000. L-leucine availability regulates phosphatidylinositol 3-kinase, P70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: Evidence for the involvement of the mammalian target of rapamycin (MTOR) pathway in the L-leucine-induced up-regulation of System A amino acid transport. Biochemical Journal 350 (2):361–8. doi: 10.1042/0264-6021:3500361.
   PubMedGoogle Scholar
• Piccolo, B. D., K. B. Comerford, S. E. Karakas, T. A. Knotts, O. Fiehn, and S. H. Adams. 2015. Whey protein supplementation does not alter plasma branched-chained amino acid profiles but results in unique metabolomics patterns in obese women enrolled in an 8-week weight loss trial. The Journal of Nutrition 145 (4):691–700. doi: 10.3945/jn.114.203943.
   PubMed Web of Science ®Google Scholar
• Polis, B., and A. O. Samson. 2020. Role of the metabolism of branched-chain amino acids in the development of Alzheimer’s disease and other metabolic disorders. Neural Regeneration Research 15 (8):1460–70. doi: 10.4103/1673-5374.274328.
   PubMed Web of Science ®Google Scholar
• Prosdocimo, D. A., P. Anand, X. Liao, H. Zhu, S. Shelkay, P. Artero-Calderon, L. Zhang, J. Kirsh, D. Moore, M. G. Rosca, et al. 2014. Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. The Journal of Biological Chemistry 289 (9):5914–24. doi: 10.1074/jbc.M113.531384.
   PubMed Web of Science ®Google Scholar
• Purpera, M. N., L. Shen, M. Taghavi, H. Münzberg, R. J. Martin, S. M. Hutson, and C. D. Morrison. 2012. Impaired branched chain amino acid metabolism alters feeding behavior and increases orexigenic neuropeptide expression in the hypothalamus. Journal of Endocrinology 212 (1):85–94. doi: 10.1530/JOE-11-0270.
   PubMed Web of Science ®Google Scholar
• Qin, L.‐Q., P. Xun, D. Bujnowski, M. L. Daviglus, L. Van Horn, J. Stamler, and K. He. 2011. Higher branched-chain amino acid intake is associated with a lower prevalence of being overweight or obese in middle-aged East Asian and Western adults. The Journal of Nutrition 141 (2):249–54. doi: 10.3945/jn.110.128520.
   PubMed Web of Science ®Google Scholar
• Rabaglia, M. E., M. P. Gray-Keller, B. L. Frey, M. R. Shortreed, L. M. Smith, and A. D. Attie. 2005. Alpha-ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice. American Journal of Physiology. Endocrinology and Metabolism 289 (2):E218–E224. doi: 10.1152/ajpendo.00573.2004.
   PubMed Web of Science ®Google Scholar
• Ramzan, I., M. Taylor, B. Phillips, D. Wilkinson, K. Smith, I. Idris, P. Atherton, and K. Hession. 2020. A novel dietary intervention reduces circulatory branched-chain amino acids by 50%: A pilot study of relevance for obesity and diabetes. Nutrients 13 (1):95. doi: 10.3390/nu13010095.
   PubMed Web of Science ®Google Scholar
• Rawat, A. K., V. Korthikunta, S. Gautam, S. Pal, N. Tadigoppula, A. K. Tamrakar, and A. K. Srivastava. 2014. 4-hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway. Fitoterapia 99 (December):307–17. doi: 10.1016/j.fitote.2014.10.006.
   PubMedGoogle Scholar
• Ricoult, S. J. H., and B. D. Manning. 2013. The multifaceted role of MTORC1 in the control of lipid metabolism. EMBO Reports 14 (3):242–51. doi: 10.1038/embor.2013.5.
   PubMed Web of Science ®Google Scholar
• Ridaura, V. K., J. J. Faith, F. E. Rey, J. Cheng, A. E. Duncan, A. L. Kau, N. W. Griffin, V. Lombard, B. Henrissat, J. R. Bain, et al. 2013. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341 (6150):1241214. doi:10.1126/science.
   PubMed Web of Science ®Google Scholar
• Rivera, M. E., E. S. Lyon, M. A. Johnson, and R. A. Vaughan. 2020. Leucine increases mitochondrial metabolism and lipid content without altering insulin signaling in myotubes. Biochimie 168 (January):124–33. doi: 10.1016/j.biochi.2019.10.017.
   PubMedGoogle Scholar
• Roberts, L. D., P. Boström, J. F. O’Sullivan, R. T. Schinzel, G. D. Lewis, A. Dejam, Y.-K. Lee, M. J. Palma, S. Calhoun, A. Georgiadi, et al. 2014. β-aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metabolism 19 (1):96–108. doi: 10.1016/j.cmet.2013.12.003.
   PubMed Web of Science ®Google Scholar
• Roquetto, A. R., C. S. Moura, V. de Almeida Santos-Junior, P. O. S. Oliveira, K. I. A. Machado, G. C. B. C. Carvalho, E. M. Risso, and J. Amaya-Farfan. 2020. Moderate intake of BCAA-rich protein improves glucose homeostasis in high-fat-fed mice. The Journal of Nutritional Biochemistry 80 (June):108332. doi: 10.1016/j.jnutbio.2019.108332.
   PubMedGoogle Scholar
• Ruderman, N. B., X. J. Xu, L. Nelson, J. M. Cacicedo, A. K. Saha, F. Lan, and Y. Ido. 2010. AMPK and SIRT1: A long-standing partnership?American Journal of Physiology 298 (4):E751–E760. doi: 10.1152/ajpendo.00745.2009.
   PubMed Web of Science ®Google Scholar
• Ruskovska, T., and D. A. Bernlohr. 2013. Oxidative stress and protein carbonylation in adipose tissue—Implications for insulin resistance and diabetes mellitus. Journal of Proteomics 92 (October):323–34. doi: 10.1016/j.jprot.2013.04.002.
   PubMedGoogle Scholar
• Saha, A., K. Coughlan, R. Valentine, and N. Ruderman. 2014. AMPK activation: A therapeutic target for type 2 diabetes?Diabetes, Metabolic Syndrome and Obesity 7:241–53. doi: 10.2147/DMSO.S43731.
   PubMedGoogle Scholar
• Sánchez-González, C., C. Nuevo-Tapioles, J. C. Herrero Martín, M. P. Pereira, S. Serrano Sanz, A. Ramírez de Molina, J. M. Cuezva, and L. Formentini. 2020. Dysfunctional oxidative phosphorylation shunts branched-chain amino acid catabolism onto lipogenesis in skeletal muscle. The EMBO Journal 39 (14):e103812. doi: 10.15252/embj.2019103812.
   PubMed Web of Science ®Google Scholar
• Sans, R. M., W. W. Jolly, and R. A. Harris. 1980. Studies on the regulation of leucine catabolism. Mechanism Responsible for oxidizable substrate inhibition and dichloroacetate stimulation of leucine oxidation by the heart. Archives of Biochemistry and Biophysics 200 (2):336–45. doi: 10.1016/0003-9861(80)90363-X.
   PubMed Web of Science ®Google Scholar
• Sato, Y., H. Tate, F. Yoshizawa, and Y. Sato. 2020. Data on the proliferation and differentiation of C2C12 myoblast treated with branched-chain ketoacid dehydrogenase kinase inhibitor. Data Brief 31 (August):105766. 105766. doi: 10.1016/j.dib.2020.105766.
   PubMedGoogle Scholar
• Satomi, S., A. Morio, H. Miyoshi, R. Nakamura, R. Tsutsumi, H. Sakaue, T. Yasuda, N. Saeki, and Y. M. Tsutsumi. 2020. Branched-chain amino acids-induced cardiac protection against ischemia/reperfusion injury. Life Sciences 245 (March):117368. doi: 10.1016/j.lfs.2020.117368.
   PubMedGoogle Scholar
• Saxton, R. A., and D. M. Sabatini. 2017. MTOR signaling in growth, metabolism, and disease. Cell 168 (6):960–76. doi: 10.1016/j.cell.2017.02.004.
   PubMed Web of Science ®Google Scholar
• Scalise, M., M. Galluccio, L. Console, L. Pochini, and C. Indiveri. 2018. The human SLC7A5 (LAT1): The intriguing histidine/large neutral amino acid transporter and its relevance to human health. Frontiers in Chemistry 6 (JUN):243. doi: 10.3389/fchem.2018.00243.
   PubMedGoogle Scholar
• Scott, L. J. 2017. Sitagliptin: A review in type 2 diabetes. Drugs 77 (2):209–24. doi: 10.1007/s40265-016-0686-9.
   PubMed Web of Science ®Google Scholar
• Sears, D. D., G. Hsiao, A. Hsiao, J. G. Yu, C. H. Courtney, J. M. Ofrecio, J. Chapman, and S. Subramaniam. 2009. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization. Proceedings of the National Academy of Sciences of the United States of America 106 (44):18745–50. doi: 10.1073/pnas.0903032106.
   PubMed Web of Science ®Google Scholar
• Serralde-Zúñiga, A. E., M. Guevara-Cruz, A. R. Tovar, M. F. Herrera-Hernández, L. G. Noriega, O. Granados, and N. Torres. 2014. Omental adipose tissue gene expression, gene variants, branched-chain amino acids, and their relationship with metabolic syndrome and insulin resistance in humans. Genes & Nutrition 9 (6):1–10. doi: 10.1007/s12263-014-0431-5.
   Web of Science ®Google Scholar
• Seyfried, F., J. Phetcharaburanin, M. Glymenaki, A. Nordbeck, M. Hankir, J. K. Nicholson, E. Holmes, J. R. Marchesi, and J. V. Li. 2021. Roux-En-Y gastric bypass surgery in zucker rats induces bacterial and systemic metabolic changes independent of caloric restriction-induced weight loss. Gut Microbes 13 (1):1–20. doi: 10.1080/19490976.2021.1875108.
   PubMed Web of Science ®Google Scholar
• Shan, Y., Y. Gao, W. Jin, M. Fan, Y. Wang, Y. Gu, C. Shan, L. Sun, X. Li, B. Yu, et al. 2019. Targeting HIBCH to reprogram valine metabolism for the treatment of colorectal cancer. Cell Death & Disease 10 (8):618. doi: 10.1038/s41419-019-1832-6.
   PubMedGoogle Scholar
• Shao, D., O. Villet, Z. Zhang, S. W. Choi, J. Yan, J. Ritterhoff, H. Gu, D. Djukovic, D. Christodoulou, S. C. Kolwicz, et al. 2018. Glucose promotes cell growth by suppressing branched-chain amino acid degradation. Nature Communications 9 (1):2935. doi: 10.1038/s41467-018-05362-7.
   PubMedGoogle Scholar
• She, P., K. C. Olson, Y. Kadota, A. Inukai, Y. Shimomura, C. L. Hoppel, S. H. Adams, Y. Kawamata, H. Matsumoto, R. Sakai, et al. 2013. Leucine and protein metabolism in obese zucker rats. PLoS One 8 (3):e59443. doi: 10.1371/journal.pone.0059443.
   PubMed Web of Science ®Google Scholar
• She, P., T. M. Reid, S. K. Bronson, T. C. Vary, A. Hajnal, C. J. Lynch, and S. M. Hutson. 2007. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metabolism 6 (3):181–94. doi: 10.1016/j.cmet.2007.08.003.
   PubMed Web of Science ®Google Scholar
• She, P., C. Van Horn, T. Reid, S. M. Hutson, R. N. Cooney, and C. J. Lynch. 2007. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. American Journal of Physiology. Endocrinology and Metabolism 293 (6):E1552–E1563. doi: 10.1152/ajpendo.00134.2007.
   PubMed Web of Science ®Google Scholar
• She, P., Y. Zhou, Z. Zhang, K. Griffin, K. Gowda, and C. J. Lynch. 2010. Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance. Journal of Applied Physiology 108 (4):941–9. doi: 10.1152/japplphysiol.01248.2009.
   PubMed Web of Science ®Google Scholar
• Shi, C.-X., M.-X. Zhao, X.-D. Shu, X.-Q. Xiong, J.-J. Wang, X.-Y. Gao, Q. Chen, Y.-H. Li, Y.-M. Kang, and G.-Q. Zhu. 2016. β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes. Scientific Reports 6:21924. doi: 10.1038/srep21924.
   PubMed Web of Science ®Google Scholar
• Shin, A. C., M. Fasshauer, N. Filatova, L. A. Grundell, E. Zielinski, J.-Y. Zhou, T. Scherer, C. Lindtner, P. J. White, A. L. Lapworth, et al. 2014. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metabolism 20 (5):898–909. doi: 10.1016/j.cmet.2014.09.003.
   PubMed Web of Science ®Google Scholar
• Shou, J., P.-J. Chen, and W.-H. Xiao. 2019. The effects of BCAAs on insulin resistance in athletes. Journal of Nutritional Science and Vitaminology 65 (5):383–9. doi: 10.3177/jnsv.65.383.
   PubMed Web of Science ®Google Scholar
• Siddik, M. A. B., and A. C. Shin. 2019. Recent progress on branched-chain amino acids in obesity, diabetes, and beyond. Endocrinology and Metabolism 34 (3):234–46. doi: 10.3803/EnM.2019
   Web of Science ®Google Scholar
• Simpson, S. J., and D. Raubenheimer. 2005. Obesity: The protein leverage hypothesis. Obesity Reviews 6 (2):133–42. doi: 10.1111/j.1467-789X.2005.00178.x.
   PubMed Web of Science ®Google Scholar
• Sohn, J.-W. 2015. Network of hypothalamic neurons that control appetite. BMB Reports 48 (4):229–33. doi: 10.5483/BMBRep.2015.48.4.272.
   PubMed Web of Science ®Google Scholar
• Solerte, S. B., M. Fioravanti, E. Locatelli, R. Bonacasa, M. Zamboni, C. Basso, A. Mazzoleni, V. Mansi, N. Geroutis, and C. Gazzaruso. 2008. Improvement of blood glucose control and insulin sensitivity during a long-term (60 weeks) randomized study with amino acid dietary supplements in elderly subjects with type 2 diabetes mellitus. The American Journal of Cardiology 101 (11A):82E–88E. doi: 10.1016/j.amjcard.2008.03.006.
   PubMed Web of Science ®Google Scholar
• Solon-Biet, S. M., V. C. Cogger, T. Pulpitel, D. Wahl, X. Clark, E. Bagley, G. C. Gregoriou, A. M. Senior, Q.-P. Wang, A. E. Brandon, et al. 2019. Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nature Metabolism 1 (5):532–45. doi: 10.1038/s42255-019-0059-2.
   PubMedGoogle Scholar
• Stautemas, J., A. B. P. Van Kuilenburg, L. Stroomer, F. Vaz, L. Blancquaert, F. B. D. Lefevere, I. Everaert, and W. Derave. 2019. Acute aerobic exercise leads to increased plasma levels of R- and S-β-aminoisobutyric acid in humans. Frontiers in Physiology 10 (SEP):1240. doi: 10.3389/fphys.2019.01240.
   PubMedGoogle Scholar
• Streck, E. L., F. P. Bussular, L. B. Wessler, M. B. Duarte, V. L. Rezende, M. S. Rodrigues, C. A. Torres, I. S. Lemos, G. Candiotto, F. F. Gava, et al. 2021. Administration of branched-chain amino acids alters epigenetic regulatory enzymes in an animal model of maple syrup urine disease. Metabolic Brain Disease 36 (2):247–54. doi: 10.1007/s11011-020-00631-1.
   PubMed Web of Science ®Google Scholar
• Su, X., F. Magkos, D. Zhou, J. Christopher Eagon, E. Fabbrini, A. L. Okunade, and S. Klein. 2015. Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss. Obesity 23 (2):329–34. doi: 10.1002/oby.20923.
   PubMed Web of Science ®Google Scholar
• Sugawara, T., Y. Ito, N. Nishizawa, and T. Nagasawa. 2009. Regulation of muscle protein degradation, not synthesis, by dietary leucine in rats fed a protein-deficient diet. Amino Acids 37 (4):609–16. doi: 10.1007/s00726-008-0180-0.
   PubMed Web of Science ®Google Scholar
• Sun, H., K. C. Olson, C. Gao, D. A. Prosdocimo, M. Zhou, Z. Wang, D. Jeyaraj, J.-Y. Youn, S. Ren, Y. Liu, et al. 2016. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133 (21):2038–49. doi: 10.1161/CIRCULATIONAHA.115.020226.
   PubMed Web of Science ®Google Scholar
• Sunny, N. E., S. Kalavalapalli, F. Bril, T. J. Garrett, M. Nautiyal, J. T. Mathew, C. M. Williams, and K. Cusi. 2015. Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease. American Journal of Physiology. Endocrinology and Metabolism 309 (4):E311–E319. doi: 10.1152/ajpendo.00161.2015.
   PubMed Web of Science ®Google Scholar
• Supruniuk, E., A. Mikłosz, and A. Chabowski. 2020. Pyrroloquinoline quinone modifies lipid profile, but not insulin sensitivity, of palmitic acid-treated L6 myotubes. International Journal of Molecular Sciences 21 (21):8382. doi: 10.3390/ijms21218382.
   PubMed Web of Science ®Google Scholar
• Szkudelska, K., L. Nogowski, and T. Szkudelski. 2014. Adipocyte dysfunction in rats with streptozotocin-nicotinamide-induced diabetes. International Journal of Experimental Pathology 95 (2):86–94. doi: 10.1111/iep.12073.
   PubMed Web of Science ®Google Scholar
• Taghavi, M., and S. Hutson. 2012. Generation of branched chain Α‐keto acid dehydrogenase enzyme complex E1α knockout mouse models. The FASEB Journal 26 (S1):1013.24. doi: 10.1096/fasebj.26.1_supplement.1013.24.
   Google Scholar
• Tamanna, N., and N. Mahmood. 2014. Emerging roles of branched-chain amino acid supplementation in human diseases. International Scholarly Research Notices 2014 (November):235619. doi: 10.1155/2014/235619.
   PubMedGoogle Scholar
• Tan, H. C., J. W. Hsu, C. M. Khoo, E. Shyong Tai, S. Yu, S. Chacko, O. F. Lai, and F. Jahoor. 2018. Alterations in branched-chain amino acid kinetics in nonobese but insulin-resistant Asian men. The American Journal of Clinical Nutrition 108 (6):1220–8. doi: 10.1093/ajcn/nqy208.
   PubMed Web of Science ®Google Scholar
• Tan, H. C., J. W. Hsu, J.-P. Kovalik, A. Eng, W. H. Chan, C. M. Khoo, E. S. Tai, S. Chacko, and F. Jahoor. 2020. Branched-chain amino acid oxidation is elevated in adults with morbid obesity and decreases significantly after sleeve gastrectomy. The Journal of Nutrition 150 (12):3180–9. doi: 10.1093/jn/nxaa298.
   PubMed Web of Science ®Google Scholar
• Taneera, J., S. Lang, A. Sharma, J. Fadista, Y. Zhou, E. Ahlqvist, A. Jonsson, V. Lyssenko, P. Vikman, O. Hansson, et al. 2012. A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metabolism 16 (1):122–34. doi: 10.1016/j.cmet.2012.06.006.
   PubMed Web of Science ®Google Scholar
• Terakura, D., M. Shimizu, J. Iwasa, A. Baba, T. Kochi, T. Ohno, M. Kubota, Y. Shirakami, M. Shiraki, K. Takai, et al. 2012. Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-Db/Db obese mice. Carcinogenesis 33 (12):2499–506. doi: 10.1093/carcin/bgs303.
   PubMed Web of Science ®Google Scholar
• Tobias, D. K., A. Hazra, P. R. Lawler, P. D. Chandler, D. I. Chasman, J. E. Buring, I. Min Lee, S. Cheng, A. E. Jo, S. Manson, et al. 2020. Circulating branched-chain amino acids and long-term risk of obesity-related cancers in women. Scientific Reports 10 (1):16534. doi: 10.1038/s41598-020-73499-x.
   PubMed Web of Science ®Google Scholar
• Tobias, D. K., S. Mora, S. Verma, F. Billia, J. E. Buring, and P. R. Lawler. 2021. Fasting status and metabolic health in relation to plasma branched chain amino acid concentrations in women. Metabolism 117 (April):154391. doi: 10.1016/j.metabol.2020.154391.
   PubMedGoogle Scholar
• Torres-Leal, F. L., M. H. Fonseca-Alaniz, G. F. Teodoro, M. D. De Capitani, D. Vianna, L. C. Pantaleão, E. M. Matos-Neto, M. M. Rogero, J. Donato, and J. Tirapegui. 2011. Leucine supplementation improves adiponectin and total cholesterol concentrations despite the lack of changes in adiposity or glucose homeostasis in rats previously exposed to a high-fat diet. Nutrition & Metabolism 8 (1):62. doi: 10.1186/1743-7075-8-62.
   PubMedGoogle Scholar
• Townsend, J. R., M. S. Fragala, A. R. Jajtner, A. M. Gonzalez, A. J. Wells, G. T. Mangine, E. H. Robinson, W. P. McCormack, K. S. Beyer, G. J. Pruna, et al. 2013. β-hydroxy-β-methylbutyrate (HMB)-free acid attenuates circulating TNF-α and TNFR1 expression postresistance exercise. Journal of Applied Physiology 115 (8):1173–82. doi: 10.1152/japplphysiol.00738.2013.
   PubMed Web of Science ®Google Scholar
• Tso, S.-C., W.-J. Gui, C.-Y. Wu, J. L. Chuang, X. Qi, K. J. Skvora, K. Dork, A. L. Wallace, L. K. Morlock, B. H. Lee, et al. 2014. Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase. The Journal of Biological Chemistry 289 (30):20583–93. doi: 10.1074/jbc.M114.569251.
   PubMed Web of Science ®Google Scholar
• Uddin, G. M., S. Pherwani, C. S. Wagg, K. Gopal, R. A. Batran, L. Zhang, Y. Wu, N. Hussaini, S. Rawat, J. R. Ussher, et al. 2019. A cardiac specific branched chain aminotransferase deletion increases insulin stimulated glucose oxidation in the mouse heart. Circulation Research 125 (Suppl_1):868. doi: 10.1161/res.125.suppl_1.868.
   Google Scholar
• Uddin, G. M., L. Zhang, S. Shah, A. Fukushima, C. S. Wagg, K. Gopal, R. Al Batran, S. Pherwani, K. L. Ho, J. Boisvenue, et al. 2019. Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure. Cardiovascular Diabetology 18 (1):86. doi: 10.1186/s12933-019-0892-3.
   PubMedGoogle Scholar
• Valerio, A., G. D’Antona, and E. Nisoli. 2011. Branched-chain amino acids, mitochondrial biogenesis, and healthspan: An evolutionary perspective. Aging 3 (5):464–78. doi: 10.18632/aging.100322.
   PubMedGoogle Scholar
• Vangipurapu, J., A. Stancáková, U. Smith, J. Kuusisto, and M. Laakso. 2019. Nine amino acids are associated with decreased insulin secretion and elevated glucose levels in a 7.4-year follow-up study of 5,181 Finnish men. Diabetes 68 (6):1353–8. doi: 10.2337/db18-1076.
   PubMed Web of Science ®Google Scholar
• Vanweert, F., S. C. Boone, B. Brouwers, D. O. Mook-Kanamori, R. de Mutsert, F. R. Rosendaal, H. J. Lamb, V. B. Schrauwen-Hinderling, P. Schrauwen, M. K. C. Hesselink, et al. 2021. The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity. International Journal of Obesity 45 (7):1510–20. doi: 10.1038/s41366-021-00815-4.
   Web of Science ®Google Scholar
• Wagenmakers, A. J. M. 1998. Muscle amino acid metabolism at rest and during exercise: Role in human physiology and metabolism. Exercise and Sport Sciences Reviews 26:287–314. https://pubmed.ncbi.nlm.nih.gov/9696993/. doi: 10.1249/00003677-199800260-00013.
   PubMed Web of Science ®Google Scholar
• Walejko, J. M., B. A. Christopher, S. B. Crown, G.-F. Zhang, A. Pickar-Oliver, T. Yoneshiro, M. W. Foster, S. Page, S. van Vliet, O. Ilkayeva, et al. 2021. Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart. Nature Communications 12 (1):1680–14. doi: 10.1038/s41467-021-21962-2.
   PubMed Web of Science ®Google Scholar
• Walford, G. A., J. Davis, A. S. Warner, R. J. Ackerman, L. K. Billings, B. Chamarthi, R. R. Fanelli, A. M. Hernandez, C. Huang, S. Q. Khan, et al. 2013. Branched chain and aromatic amino acids change acutely following two medical therapies for type 2 diabetes mellitus. Metabolism 62 (12):1772–8. doi: 10.1016/j.metabol.2013.07.003.
   PubMed Web of Science ®Google Scholar
• Walker, D. K., M. J. Drummond, J. M. Dickinson, M. S. Borack, K. Jennings, E. Volpi, and B. B. Rasmussen. 2014. Insulin increases MRNA abundance of the amino acid transporter SLC7A5/LAT1 via an MTORC1-dependent mechanism in skeletal muscle cells. Physiological Reports 2 (3):e00238. doi: 10.1002/phy2.238.
   PubMedGoogle Scholar
• Wallace, M., C. R. Green, L. S. Roberts, Y. M. Lee, J. L. McCarville, J. Sanchez-Gurmaches, N. Meurs, J. M. Gengatharan, J. D. Hover, S. A. Phillips, et al. 2018. Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nature Chemical Biology 14 (11):1021–31. doi: 10.1038/s41589-018-0132-2.
   PubMed Web of Science ®Google Scholar
• Wanders, D., K. P. Stone, K. Dille, J. Simon, A. Pierse, and T. W. Gettys. 2015. Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling. BioFactors 41 (6):391–402. doi: 10.1002/biof.1240.
   PubMed Web of Science ®Google Scholar
• Wang, J., Y. Liu, K. Lian, X. Shentu, J. Fang, J. Shao, M. Chen, Y. Wang, M. Zhou, and H. Sun. 2019. BCAA catabolic defect alters glucose metabolism in lean mice. Frontiers in Physiology 10 (September):1140. doi: 10.3389/fphys.2019.01140.
   PubMedGoogle Scholar
• Wang, T. J., M. G. Larson, R. S. Vasan, S. Cheng, E. P. Rhee, E. McCabe, G. D. Lewis, C. S. Fox, P. F. Jacques, C. Fernandez, et al. 2011. Metabolite profiles and the risk of developing diabetes. Nature Medicine 17 (4):448–53. doi: 10.1038/nm.2307.
   PubMed Web of Science ®Google Scholar
• Watterson, K. R., D. Bestow, J. Gallagher, D. L. Hamilton, F. B. Ashford, P. J. Meakin, and M. L. J. Ashford. 2013. Anorexigenic and orexigenic hormone modulation of mammalian target of rapamycin complex 1 activity and the regulation of hypothalamic agouti-related protein MRNA expression. Neuro-Signals 21 (1-2):28–41. doi: 10.1159/000334144.
   PubMedGoogle Scholar
• Wei, S., J. Zhao, S. Wang, M. Huang, Y. Wang, and Y. Chen. 2018. Intermittent administration of a leucine-deprived diet is able to intervene in type 2 diabetes in Db/Db mice. Heliyon 4 (9):e00830. doi: 10.1016/j.heliyon.2018.e00830.
   PubMed Web of Science ®Google Scholar
• Weickert, M. O., M. Roden, F. Isken, D. Hoffmann, P. Nowotny, M. Osterhoff, M. Blaut, C. Alpert, O. Gögebakan, C. Bumke-Vogt, et al. 2011. Effects of supplemented isoenergetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans. The American Journal of Clinical Nutrition 94 (2):459–71. doi: 10.3945/ajcn.110.004374.
   PubMed Web of Science ®Google Scholar
• White, P. J., A. L. Lapworth, J. An, L. Wang, R. W. McGarrah, R. D. Stevens, O. Ilkayeva, T. George, M. J. Muehlbauer, J. R. Bain, et al. 2016. Branched-chain amino acid restriction in zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and Acyl-glycine export. Molecular Metabolism 5 (7):538–51. doi: 10.1016/j.molmet.2016.04.006.
   PubMed Web of Science ®Google Scholar
• White, P. J., A. L. Lapworth, R. W. McGarrah, L. C. Kwee, S. B. Crown, O. Ilkayeva, J. An, M. W. Carson, B. A. Christopher, J. R. Ball, et al. 2020. Muscle-liver trafficking of BCAA-derived nitrogen underlies obesity-related glycine depletion. Cell Reports 33 (6):108375. doi: 10.1016/j.celrep.2020.108375.
   PubMed Web of Science ®Google Scholar
• White, P. J., R. W. McGarrah, P. A. Grimsrud, S.-C. Tso, W.-H. Yang, J. M. Haldeman, T. Grenier-Larouche, J. An, A. L. Lapworth, I. Astapova, et al. 2018. The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase. Cell Metabolism 27 (6):1281–93.e7. doi: 10.1016/j.cmet.2018.04.015.
   PubMed Web of Science ®Google Scholar
• Williamson, J. R., E. Wałajtys-Rode, and K. E. Coll. 1979. Effects of branched chain α-ketoacids on the metabolism of isolated rat liver cells. I. Regulation of branched chain α-ketoacid metabolism. Journal of Biological Chemistry 254 (22):11511–20. doi: 10.1016/S0021-9258(19)86514-6.
   PubMed Web of Science ®Google Scholar
• Wolfe, R. R. 2017. Branched-chain amino acids and muscle protein synthesis in humans: Myth or reality?Journal of the International Society of Sports Nutrition 14:30. doi: 10.1186/s12970-017-0184-9.
   PubMed Web of Science ®Google Scholar
• Wondmkun, Y. T. 2020. Obesity, insulin resistance, and type 2 diabetes: Associations and therapeutic implications. Diabetes, Metabolic Syndrome and Obesity 13 (October):3611–6. doi: 10.2147/DMSO.S275898.
   PubMedGoogle Scholar
• Wu, J., M. Zhao, C. Li, Y. Zhang, and D. W. Wang. 2021. The SARS-CoV-2 induced targeted amino acid profiling in patients at hospitalized and convalescent stage. Bioscience Reports 41 (3):BSR20204201. doi: 10.1042/BSR20204201.
   PubMedGoogle Scholar
• Würtz, P., Q. Wang, A. J. Kangas, R. C. Richmond, J. Skarp, M. Tiainen, T. Tynkkynen, P. Soininen, A. S. Havulinna, M. Kaakinen, et al. 2014. Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change. PLoS Medicine 11 (12):e1001765. doi: 10.1371/journal.pmed.1001765.
   PubMed Web of Science ®Google Scholar
• Xiao, F., Z. Huang, H. Li, J. Yu, C. Wang, S. Chen, Q. Meng, Y. Cheng, X. Gao, J. Li, et al. 2011. Leucine deprivation increases hepatic insulin sensitivity via GCN2/MTOR/S6K1 and AMPK pathways. Diabetes 60 (3):746–56. doi: 10.2337/db10-1246.
   PubMed Web of Science ®Google Scholar
• Xiao, F., J. Yu, Y. Guo, J. Deng, K. Li, Y. Du, S. Chen, J. Zhu, H. Sheng, and F. Guo. 2014. Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice. Metabolism 63 (6):841–50. doi: 10.1016/j.metabol.2014.03.006.
   PubMed Web of Science ®Google Scholar
• Xu, F., S. Tavintharan, C. Fang Sum, K. Woon, S. C. Lim, and C. N. Ong. 2013. Metabolic signature shift in type 2 diabetes mellitus revealed by mass spectrometry-based metabolomics. Journal of Clinical Endocrinology and Metabolism 98 (6):1060–5. doi: 10.1210/jc.2012-4132.
   PubMed Web of Science ®Google Scholar
• Xu, M., Y. Kitaura, T. Ishikawa, Y. Kadota, C. Terai, D. Shindo, T. Morioka, M. Ota, Y. Morishita, K. Ishihara, et al. 2017. Endurance performance and energy metabolism during exercise in mice with a muscle-specific defect in the control of branched-chain amino acid catabolism. PLoS One 12 (7):e0180989. doi: 10.1371/journal.pone.0180989.
   PubMed Web of Science ®Google Scholar
• Xu, M., M. Nagasaki, M. Obayashi, Y. Sato, T. Tamura, and Y. Shimomura. 2001. Mechanism of activation of branched-chain alpha-keto acid dehydrogenase complex by exercise. Biochemical and Biophysical Research Communications 287 (3):752–6. doi: 10.1006/bbrc.2001.5647.
   PubMed Web of Science ®Google Scholar
• Xu, M., Q. Qi, J. Liang, G. A. Bray, F. B. Hu, F. M. Sacks, and L. Qi. 2013. Genetic determinant for amino acid metabolites and changes in body weight and insulin resistance in response to weight-loss diets: The preventing overweight using novel dietary strategies (POUNDS LOST) trial. Circulation 127 (12):1283–9. doi: 10.1161/CIRCULATIONAHA.112.000586.
   PubMed Web of Science ®Google Scholar
• Yadav, A., N. Shah, P. Kumar Tiwari, K. Javed, Q. Cheng, I. S. Aidhen, and S. Bröer. 2020. Novel chemical scaffolds to inhibit the neutral amino acid transporter B0AT1 (SLC6A19), a potential target to treat metabolic diseases. Frontiers in Pharmacology 11 (February)::140. doi: 10.3389/fphar.2020.00140.
   PubMedGoogle Scholar
• Yang, Z., S. Huang, D. Zou, D. Dong, X. He, N. Liu, W. Liu, and L. Huang. 2016. Metabolic shifts and structural changes in the gut microbiota upon branched-chain amino acid supplementation in middle-aged mice. Amino Acids 48 (12):2731–45. doi: 10.1007/s00726-016-2308-y.
   PubMed Web of Science ®Google Scholar
• Yao, J., J. P. Kovalik, O. F. Lai, P. Ching Lee, A. Eng, W. Hoong Chan, K. W. Tham, E. Lim, Y. Mong Bee, and H. C. Tan. 2019. Comprehensive assessment of the effects of sleeve gastrectomy on glucose, lipid, and amino acid metabolism in Asian individuals with morbid obesity. Obesity Surgery 29 (1):149–58. doi: 10.1007/s11695-018-3487-2.
   PubMed Web of Science ®Google Scholar
• Yoneshiro, T., Q. Wang, K. Tajima, M. Matsushita, H. Maki, K. Igarashi, Z. Dai, P. J. White, R. W. McGarrah, O. R. Ilkayeva, et al. 2019. BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature 572 (7771):614–9. doi: 10.1038/s41586-019-1503-x.
   PubMed Web of Science ®Google Scholar
• Yu, D., N. E. Richardson, C. L. Green, A. B. Spicer, M. E. Murphy, V. Flores, C. Jang, I. Kasza, M. Nikodemova, M. H. Wakai, et al. 2021. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metabolism 33 (5):905–22.e6. doi: 10.1016/j.cmet.2021.03.025.
   PubMed Web of Science ®Google Scholar
• Yuan, X. W., S. F. Han, J. W. Zhang, J. Y. Xu, and L. Q. Qin. 2015. Leucine supplementation improves leptin sensitivity in high-fat diet fed rats. Food & Nutrition Research 59 (June):27373. doi: 10.3402/fnr.v59.27373.
   PubMedGoogle Scholar
• Yue, S.-J., J. Liu, A.-T. Wang, X.-T. Meng, Z.-R. Yang, C. Peng, H.-S. Guan, C.-Y. Wang, and D. Yan. 2019. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids. American Journal of Physiology. Endocrinology and Metabolism 316 (1):E73–E85. doi: 10.1152/ajpendo.00256.2018.
   PubMed Web of Science ®Google Scholar
• Zarfeshani, A., S. Ngo, and A. M. Sheppard. 2014. Leucine alters hepatic glucose/lipid homeostasis via the myostatin-AMP-activated protein kinase pathway: Potential implications for nonalcoholic fatty liver disease. Clinical Epigenetics 6 (1):27. doi: 10.1186/1868-7083-6-27.
   PubMedGoogle Scholar
• Zhang, B., Y. Chen, X. Shi, M. Zhou, L. Bao, K. J. Hatanpaa, T. Patel, R. J. DeBerardinis, Y. Wang, and W. Luo. 2021. Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma. Cellular and Molecular Life Sciences 78 (1):195–206. doi: 10.1007/s00018-020-03483-1.
   PubMed Web of Science ®Google Scholar
• Zhang, F., S. Zhao, W. Yan, Y. Xia, X. Chen, W. Wang, J. Zhang, C. Gao, C. Peng, F. Yan, et al. 2016. Branched chain amino acids cause liver injury in obese/diabetic mice by promoting adipocyte lipolysis and inhibiting hepatic autophagy. EBioMedicine 13 (November):157–67. doi: 10.1016/j.ebiom.2016.10.013.
   PubMedGoogle Scholar
• Zhang, Y., K. Guo, R. E. LeBlanc, D. Loh, G. J. Schwartz, and Y. H. Yu. 2007. Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56 (6):1647–54. doi: 10.2337/db07-0123.
   PubMed Web of Science ®Google Scholar
• Zhao, H., H. Li, A. C. K. Chung, L. Xiang, X. Li, Y. Zheng, H. Luan, L. Zhu, W. Liu, Y. Peng, et al. 2019. Large-scale longitudinal metabolomics study reveals different trimester-specific alterations of metabolites in relation to gestational diabetes mellitus. Journal of Proteome Research 18 (1):292–300. doi: 10.1021/acs.jproteome.8b00602.
   PubMed Web of Science ®Google Scholar
• Zhao, H., F. Zhang, D. Sun, X. Wang, X. Zhang, J. Zhang, F. Yan, C. Huang, H. Xie, C. Lin, et al. 2020. Branched-chain amino acids exacerbate obesity-related hepatic glucose and lipid metabolic disorders via attenuating Akt2 signaling. Diabetes 69 (6):1164–77. doi: 10.2337/db19-0920.
   PubMed Web of Science ®Google Scholar
• Zhao, J., B. Zhai, S. P. Gygi, and A. L. Goldberg. 2015. MTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proceedings of the National Academy of Sciences of the United States of America 112 (52):15790–7. doi: 10.1073/pnas.1521919112.
   PubMed Web of Science ®Google Scholar
• Zhao, L., M. Wang, J. Li, Y. Bi, M. Li, and J. Yang. 2019. Association of circulating branched-chain amino acids with gestational diabetes mellitus: A meta-analysis. International Journal of Endocrinology and Metabolism 17 (3):85413. doi: 10.5812/ijem.85413.
   Web of Science ®Google Scholar
• Zhao, X., Q. Han, Y. Liu, C. Sun, X. Gang, and G. Wang. 2016. The relationship between branched-chain amino acid related metabolomic signature and insulin resistance: A systematic review. Journal of Diabetes Research 2016:2794591. doi: 10.1155/2016/2794591.
   PubMed Web of Science ®Google Scholar
• Zheng, Y., Y. Li, Q. Qi, A. Hruby, J. E. Manson, W. C. Willett, B. M. Wolpin, F. B. Hu, and L. Qi. 2016. Cumulative consumption of branched-chain amino acids and incidence of type 2 diabetes. International Journal of Epidemiology 45 (5):1482–92. doi: 10.1093/ije/dyw143.
   PubMed Web of Science ®Google Scholar
• Zhou, J., J. Wu, F. Zheng, M. Jin, and H. Li. 2015. Glucagon-like peptide-1 analog-mediated protection against cholesterol-induced apoptosis via mammalian target of rapamycin activation in pancreatic ΒTC-6 cells-1mTORβTC-6. Journal of Diabetes 7 (2):231–9. doi: 10.1111/1753-0407.12177.
   PubMed Web of Science ®Google Scholar
• Zhou, M., J. Shao, C.-Y. Wu, L. Shu, W. Dong, Y. Liu, M. Chen, R. M. Wynn, J. Wang, J. Wang, et al. 2019. Targeting BCAA catabolism to treat obesity-associated insulin resistance. Diabetes 68 (9):1730–46. doi: 10.2337/db18-0927.
   PubMed Web of Science ®Google Scholar