Endocrinol Metab.  2019 Sep;34(3):234-246. 10.3803/EnM.2019.34.3.234.

Recent Progress on Branched-Chain Amino Acids in Obesity, Diabetes, and Beyond

Affiliations
  • 1Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX, USA. andrew.shin@ttu.edu

Abstract

Branched-chain amino acids (BCAAs) are essential amino acids that are not synthesized in our body; thus, they need to be obtained from food. They have shown to provide many physiological and metabolic benefits such as stimulation of pancreatic insulin secretion, milk production, adipogenesis, and enhanced immune function, among others, mainly mediated by mammalian target of rapamycin (mTOR) signaling pathway. After identified as a reliable marker of obesity and type 2 diabetes in recent years, an increasing number of studies have surfaced implicating BCAAs in the pathophysiology of other diseases such as cancers, cardiovascular diseases, and even neurodegenerative disorders like Alzheimer's disease. Here we discuss the most recent progress and review studies highlighting both correlational and potentially causative role of BCAAs in the development of these disorders. Although we are just beginning to understand the intricate relationships between BCAAs and some of the most prevalent chronic diseases, current findings raise a possibility that they are linked by a similar putative mechanism.

Keyword

Branched-chain amino acids; Metabolism; Cancers; Alzheimer disease; Heart failure

MeSH Terms

Adipogenesis
Alzheimer Disease
Amino Acids, Branched-Chain*
Amino Acids, Essential
Cardiovascular Diseases
Chronic Disease
Heart Failure
Insulin
Metabolism
Milk
Neurodegenerative Diseases
Obesity*
Sirolimus
Amino Acids, Branched-Chain
Amino Acids, Essential
Insulin
Sirolimus

Figure

  • Fig. 1 An overview of what is currently known about the role of branched-chain amino acids (BCAAs) or their derived keto-acids (i.e., branched-chain keto acids [BCKAs]) in different disease states and their potential molecular mechanisms. It is interesting to note that most studies reveal higher circulating levels of BCAAs in each disease. Items in dark blue shapes indicate mechanistic interventions based on recent studies. CNS, central nervous system; pmTOR, phosphorylated mammalian target of rapamycin; pAKT, phosphorylated protein kinase B; BCAT1, cytoplasmic branched-chain amino acid transaminase; KO, knockout; BT2, 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid; BCKDH, branched-chain α-keto acid dehydrogenase.


Reference

1. Chou PY, Fasman GD. Structural and functional role of leucine residues in proteins. J Mol Biol. 1973; 74:263–281.
Article
2. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. 1984; 4:409–454.
Article
3. Bukhari SS, Phillips BE, Wilkinson DJ, Limb MC, Rankin D, Mitchell WK, et al. Intake of low-dose leucine-rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women at rest and after exercise. Am J Physiol Endocrinol Metab. 2015; 308:E1056–E1065.
Article
4. Buse MG. In vivo effects of branched chain amino acids on muscle protein synthesis in fasted rats. Horm Metab Res. 1981; 13:502–505.
Article
5. Garlick PJ, Grant I. Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids. Biochem J. 1988; 254:579–584.
Article
6. Kobayashi H, Kato H, Hirabayashi Y, Murakami H, Suzuki H. Modulations of muscle protein metabolism by branched-chain amino acids in normal and muscle-atrophying rats. J Nutr. 2006; 136(1 Suppl):234S–236S.
Article
7. Li JB, Jefferson LS. Influence of amino acid availability on protein turnover in perfused skeletal muscle. Biochim Biophys Acta. 1978; 544:351–359.
Article
8. Louard RJ, Barrett EJ, Gelfand RA. Overnight branched-chain amino acid infusion causes sustained suppression of muscle proteolysis. Metabolism. 1995; 44:424–429.
Article
9. Matthews DE. Observations of branched-chain amino acid administration in humans. J Nutr. 2005; 135(6 Suppl):1580S–1584S.
Article
10. Buse MG, Reid SS. Leucine. A possible regulator of protein turnover in muscle. J Clin Invest. 1975; 56:1250–1261.
Article
11. Hong SO, Layman DK. Effects of leucine on in vitro protein synthesis and degradation in rat skeletal muscles. J Nutr. 1984; 114:1204–1212.
12. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012; 149:274–293.
Article
13. Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016; 351:43–48.
Article
14. Wolfe RR. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? J Int Soc Sports Nutr. 2017; 14:30.
Article
15. Chin SE, Shepherd RW, Thomas BJ, Cleghorn GJ, Patrick MK, Wilcox JA, et al. Nutritional support in children with end-stage liver disease: a randomized crossover trial of a branched-chain amino acid supplement. Am J Clin Nutr. 1992; 56:158–163.
Article
16. Habu D, Nishiguchi S, Nakatani S, Kawamura E, Lee C, Enomoto M, et al. Effect of oral supplementation with branched-chain amino acid granules on serum albumin level in the early stage of cirrhosis: a randomized pilot trial. Hepatol Res. 2003; 25:312–318.
Article
17. Tsien C, Davuluri G, Singh D, Allawy A, Ten Have GA, Thapaliya S, et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology. 2015; 61:2018–2029.
Article
18. Tietze IN, Pedersen EB. Effect of fish protein supplementation on aminoacid profile and nutritional status in haemodialysis patients. Nephrol Dial Transplant. 1991; 6:948–954.
Article
19. Choudry HA, Pan M, Karinch AM, Souba WW. Branched-chain amino acid-enriched nutritional support in surgical and cancer patients. J Nutr. 2006; 136(1 Suppl):314S–318S.
Article
20. Ishihara T, Iwasa M, Tanaka H, Kaito M, Ikoma J, Shibata T, et al. Effect of branched-chain amino acids in patients receiving intervention for hepatocellular carcinoma. World J Gastroenterol. 2014; 20:2673–2680.
Article
21. Kakazu E, Kondo Y, Kogure T, Ninomiya M, Kimura O, Iwata T, et al. Supplementation of branched-chain amino acids maintains the serum albumin level in the course of hepatocellular carcinoma recurrence. Tohoku J Exp Med. 2013; 230:191–196.
Article
22. Togo S, Tanaka K, Morioka D, Sugita M, Ueda M, Miura Y, et al. Usefulness of granular BCAA after hepatectomy for liver cancer complicated with liver cirrhosis. Nutrition. 2005; 21:480–486.
Article
23. Bower RH, Muggia-Sullam M, Vallgren S, Hurst JM, Kern KA, LaFrance R, et al. Branched chain amino acid-enriched solutions in the septic patient. A randomized, prospective trial. Ann Surg. 1986; 203:13–20.
24. Garcia-de-Lorenzo A, Ortiz-Leyba C, Planas M, Montejo JC, Nunez R, Ordonez FJ, et al. Parenteral administration of different amounts of branch-chain amino acids in septic patients: clinical and metabolic aspects. Crit Care Med. 1997; 25:418–424.
25. Jimenez Jimenez FJ, Ortiz Leyba C, Morales Menedez S, Barros Perez M, Munoz Garcia J. Prospective study on the efficacy of branched-chain amino acids in septic patients. JPEN J Parenter Enteral Nutr. 1991; 15:252–261.
Article
26. Yang J, Chi Y, Burkhardt BR, Guan Y, Wolf BA. Leucine metabolism in regulation of insulin secretion from pancreatic beta cells. Nutr Rev. 2010; 68:270–279.
Article
27. Estrada-Alcalde I, Tenorio-Guzman MR, Tovar AR, Salinas-Rubio D, Torre-Villalvazo I, Torres N, et al. Metabolic fate of branched-chain amino acids during adipogenesis, in adipocytes from obese mice and C2C12 myotubes. J Cell Biochem. 2017; 118:808–818.
Article
28. Wallace M, Green CR, Roberts LS, Lee YM, McCarville JL, Sanchez-Gurmaches J, et al. Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat Chem Biol. 2018; 14:1021–1031.
Article
29. Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, et al. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab. 2013; 304:E1175–E1187.
Article
30. Doi M, Yamaoka I, Fukunaga T, Nakayama M. Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. Biochem Biophys Res Commun. 2003; 312:1111–1117.
Article
31. Xiao F, Yu J, Guo Y, Deng J, Li K, Du Y, et al. Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice. Metabolism. 2014; 63:841–850.
Article
32. Chang Y, Cai H, Liu G, Chang W, Zheng A, Zhang S, et al. Effects of dietary leucine supplementation on the gene expression of mammalian target of rapamycin signaling pathway and intestinal development of broilers. Anim Nutr. 2015; 1:313–319.
Article
33. Zhang S, Qiao S, Ren M, Zeng X, Ma X, Wu Z, et al. Supplementation with branched-chain amino acids to a low-protein diet regulates intestinal expression of amino acid and peptide transporters in weanling pigs. Amino Acids. 2013; 45:1191–1205.
Article
34. Doelman J, Kim JJ, Carson M, Metcalf JA, Cant JP. Branched-chain amino acid and lysine deficiencies exert different effects on mammary translational regulation. J Dairy Sci. 2015; 98:7846–7855.
Article
35. Lei J, Feng D, Zhang Y, Zhao FQ, Wu Z, San Gabriel A, et al. Nutritional and regulatory role of branched-chain amino acids in lactation. Front Biosci (Landmark Ed). 2012; 17:2725–2739.
Article
36. Strathe AV, Bruun TS, Zerrahn JE, Tauson AH, Hansen CF. The effect of increasing the dietary valine-to-lysine ratio on sow metabolism, milk production, and litter growth. J Anim Sci. 2016; 94:155–164.
37. Mao X, Qi S, Yu B, He J, Yu J, Chen D. Zn(2+) and L-isoleucine induce the expressions of porcine β-defensins in IPEC-J2 cells. Mol Biol Rep. 2013; 40:1547–1552.
Article
38. Rivas-Santiago CE, Rivas-Santiago B, Leon DA, Castaneda-Delgado J, Hernandez Pando R. Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. Clin Exp Immunol. 2011; 164:80–89.
Article
39. Neis EP, Dejong CH, Rensen SS. The role of microbial amino acid metabolism in host metabolism. Nutrients. 2015; 7:2930–2946.
Article
40. Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016; 535:376–381.
Article
41. Zhang S, Zeng X, Ren M, Mao X, Qiao S. Novel metabolic and physiological functions of branched chain amino acids: a review. J Anim Sci Biotechnol. 2017; 8:10.
Article
42. Holecek M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab (Lond). 2018; 15:33.
Article
43. Bifari F, Nisoli E. Branched-chain amino acids differently modulate catabolic and anabolic states in mammals: a pharmacological point of view. Br J Pharmacol. 2017; 174:1366–1377.
Article
44. Hutson SM, Sweatt AJ, Lanoue KF. Branched-chain [corrected] amino acid metabolism: implications for establishing safe intakes. J Nutr. 2005; 135(6 Suppl):1557S–1564S.
45. Shimomura Y, Obayashi M, Murakami T, Harris RA. Regulation of branched-chain amino acid catabolism: nutritional and hormonal regulation of activity and expression of the branched-chain alpha-keto acid dehydrogenase kinase. Curr Opin Clin Nutr Metab Care. 2001; 4:419–423.
46. Arany Z, Neinast M. Branched chain amino acids in metabolic disease. Curr Diab Rep. 2018; 18:76.
Article
47. Blackburn PR, Gass JM, Vairo FPE, Farnham KM, Atwal HK, Macklin S, et al. Maple syrup urine disease: mechanisms and management. Appl Clin Genet. 2017; 10:57–66.
Article
48. Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med. 1969; 281:811–816.
Article
49. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007; 293:E1552–E1563.
Article
50. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009; 9:311–326.
Article
51. Kim JY, Park JY, Kim OY, Ham BM, Kim HJ, Kwon DY, et al. Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). J Proteome Res. 2010; 9:4368–4375.
Article
52. Mihalik SJ, Goodpaster BH, Kelley DE, Chace DH, Vockley J, Toledo FG, et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring). 2010; 18:1695–1700.
Article
53. Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE, et al. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr. 2009; 139:1073–1081.
54. Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia. 2010; 53:757–767.
Article
55. Shi L, Brunius C, Lehtonen M, Auriola S, Bergdahl IA, Rolandsson O, et al. Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort. Diabetologia. 2018; 61:849–861.
Article
56. Trico D, Prinsen H, Giannini C, de Graaf R, Juchem C, Li F, et al. Elevated α-hydroxybutyrate and branched-chain amino acid levels predict deterioration of glycemic control in adolescents. J Clin Endocrinol Metab. 2017; 102:2473–2481.
57. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011; 17:448–453.
Article
58. Lu Y, Wang Y, Ong CN, Subramaniam T, Choi HW, Yuan JM, et al. Metabolic signatures and risk of type 2 diabetes in a Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS. Diabetologia. 2016; 59:2349–2359.
Article
59. Wurtz P, Soininen P, Kangas AJ, Ronnemaa T, Lehtimaki T, Kahonen M, et al. Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults. Diabetes Care. 2013; 36:648–655.
Article
60. McCormack SE, Shaham O, McCarthy MA, Deik AA, Wang TJ, Gerszten RE, et al. Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents. Pediatr Obes. 2013; 8:52–61.
Article
61. Jeganathan S, Abdullahi A, Zargar S, Maeda N, Riddell MC, Adegoke OA. Amino acid-induced impairment of insulin sensitivity in healthy and obese rats is reversible. Physiol Rep. 2014; 2:e12067.
Article
62. Funchal C, Latini A, Jacques-Silva MC, Dos Santos AQ, Buzin L, Gottfried C, et al. Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int. 2006; 49:640–650.
63. Bridi R, Braun CA, Zorzi GK, Wannmacher CM, Wajner M, Lissi EG, et al. Alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats. Metab Brain Dis. 2005; 20:155–167.
64. Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, et al. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009; 119:1678–1687.
Article
65. Oyarzabal A, Martinez-Pardo M, Merinero B, Navarrete R, Desviat LR, Ugarte M, et al. 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. Hum Mutat. 2013; 34:355–362.
66. Amaral AU, Leipnitz G, Fernandes CG, Seminotti B, Schuck PF, Wajner M. Alpha-ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain. Brain Res. 2010; 1324:75–84.
67. Lu G, Ren S, Korge P, Choi J, Dong Y, Weiss J, et al. A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development. Genes Dev. 2007; 21:784–796.
Article
68. Jouvet P, Rustin P, Taylor DL, Pocock JM, Felderhoff-Mueser U, Mazarakis ND, et al. Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell. 2000; 11:1919–1932.
69. Jouvet P, Kozma M, Mehmet H. Primary human fibroblasts from a maple syrup urine disease patient undergo apoptosis following exposure to physiological concentrations of branched chain amino acids. Ann N Y Acad Sci. 2000; 926:116–121.
Article
70. Balage M, Dupont J, Mothe-Satney I, Tesseraud S, Mosoni L, Dardevet D. Leucine supplementation in rats induced a delay in muscle IR/PI3K signaling pathway associated with overall impaired glucose tolerance. J Nutr Biochem. 2011; 22:219–226.
Article
71. Nicastro H, Zanchi NE, da Luz CR, de Moraes WM, Ramona P, de Siqueira Filho MA, et al. Effects of leucine supplementation and resistance exercise on dexamethasone-induced muscle atrophy and insulin resistance in rats. Nutrition. 2012; 28:465–471.
Article
72. Zanchi NE, Guimaraes-Ferreira L, de Siqueira-Filho MA, Felitti V, Nicastro H, Bueno C, et al. Dose and latency effects of leucine supplementation in modulating glucose homeostasis: opposite effects in healthy and glucocorticoid-induced insulin-resistance states. Nutrients. 2012; 4:1851–1867.
Article
73. Saha AK, Xu XJ, Lawson E, Deoliveira R, Brandon AE, Kraegen EW, et al. Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes. 2010; 59:2426–2434.
Article
74. Jang C, Oh SF, Wada S, Rowe GC, Liu L, Chan MC, et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med. 2016; 22:421–426.
75. Lerin C, Goldfine AB, Boes T, Liu M, Kasif S, Dreyfuss JM, et al. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab. 2016; 5:926–936.
Article
76. Moghei M, Tavajohi-Fini P, Beatty B, Adegoke OA. Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner. Am J Physiol Cell Physiol. 2016; 311:C518–C527.
Article
77. Zhang F, Zhao S, Yan W, Xia Y, Chen X, Wang W, et al. Branched chain amino acids cause liver injury in obese/diabetic mice by promoting adipocyte lipolysis and inhibiting hepatic autophagy. EBioMedicine. 2016; 13:157–167.
Article
78. Xiao F, Huang Z, Li H, Yu J, Wang C, Chen S, et al. Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes. 2011; 60:746–756.
Article
79. White PJ, Lapworth AL, An J, Wang L, McGarrah RW, Stevens RD, et al. Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export. Mol Metab. 2016; 5:538–551.
Article
80. Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol. 2018; 596:623–645.
Article
81. Newgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 2012; 15:606–614.
Article
82. Fabbrini E, Magkos F, Conte C, Mittendorfer B, Patterson BW, Okunade AL, et al. Validation of a novel index to assess insulin resistance of adipose tissue lipolytic activity in obese subjects. J Lipid Res. 2012; 53:321–324.
Article
83. Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989; 84:205–213.
Article
84. Barazzoni R, Kiwanuka E, Zanetti M, Cristini M, Vettore M, Tessari P. Insulin acutely increases fibrinogen production in individuals with type 2 diabetes but not in individuals without diabetes. Diabetes. 2003; 52:1851–1856.
Article
85. Tessari P, Coracina A, Kiwanuka E, Vedovato M, Vettore M, Valerio A, et al. Effects of insulin on methionine and homocysteine kinetics in type 2 diabetes with nephropathy. Diabetes. 2005; 54:2968–2976.
Article
86. Halvatsiotis PG, Turk D, Alzaid A, Dinneen S, Rizza RA, Nair KS. Insulin effect on leucine kinetics in type 2 diabetes mellitus. Diabetes Nutr Metab. 2002; 15:136–142.
87. Luzi L, Petrides AS, De Fronzo RA. Different sensitivity of glucose and amino acid metabolism to insulin in NIDDM. Diabetes. 1993; 42:1868–1877.
Article
88. Biolo G, Tessari P, Inchiostro S, Bruttomesso D, Sabadin L, Fongher C, et al. Fasting and postmeal phenylalanine metabolism in mild type 2 diabetes. Am J Physiol. 1992; 263(5 Pt 1):E877–E883.
Article
89. Tessari P, Cecchet D, Cosma A, Puricelli L, Millioni R, Vedovato M, et al. Insulin resistance of amino acid and protein metabolism in type 2 diabetes. Clin Nutr. 2011; 30:267–272.
Article
90. Pietilainen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keranen H, et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med. 2008; 5:e51.
Article
91. Shin AC, Fasshauer M, Filatova N, Grundell LA, Zielinski E, Zhou JY, et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 2014; 20:898–909.
Article
92. Zhou M, Jing S, Wu CY, Shu L, Dong W, Liu Y, et al. Targeting BCAA catabolism to treat obesity-associated insulin resistance. Diabetes. 2019; 68:1730–1746.
Article
93. Schauder P, Schroder K, Matthaei D, Henning HV, Langenbeck U. Influence of insulin on blood levels of branched chain keto and amino acids in man. Metabolism. 1983; 32:323–327.
Article
94. Tessari P, Nosadini R, Trevisan R, De Kreutzenberg SV, Inchiostro S, Duner E, et al. Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism. J Clin Invest. 1986; 77:1797–1804.
Article
95. Caballero B, Wurtman RJ. Differential effects of insulin resistance on leucine and glucose kinetics in obesity. Metabolism. 1991; 40:51–58.
Article
96. Forlani G, Vannini P, Marchesini G, Zoli M, Ciavarella A, Pisi E. Insulin-dependent metabolism of branched-chain amino acids in obesity. Metabolism. 1984; 33:147–150.
Article
97. Sohn JW. Network of hypothalamic neurons that control appetite. BMB Rep. 2015; 48:229–233.
Article
98. Rui L. Brain regulation of energy balance and body weight. Rev Endocr Metab Disord. 2013; 14:387–407.
Article
99. Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med. 2014; 20:1193–1198.
Article
100. Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, Bauer MR, et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science. 2016; 353:1161–1165.
Article
101. Wang ZQ, Faddaoui A, Bachvarova M, Plante M, Gregoire J, Renaud MC, et al. BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism. Oncotarget. 2015; 6:31522–31543.
Article
102. Zheng YH, Hu WJ, Chen BC, Grahn TH, Zhao YR, Bao HL, et al. BCA.T1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. Liver Int. 2016; 36:1836–1847.
Article
103. Zhang L, Han J. Branched-chain amino acid transaminase 1 (BCAT1) promotes the growth of breast cancer cells through improving mTOR-mediated mitochondrial biogenesis and function. Biochem Biophys Res Commun. 2017; 486:224–231.
Article
104. Ericksen RE, Lim SL, McDonnell E, Shuen WH, Vadiveloo M, White PJ, et al. Loss of BCAA catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression. Cell Metab. 2019; 29:1151–1165.
Article
105. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004; 18:1926–1945.
Article
106. Hunter WG, Kelly JP, McGarrah RW 3rd, Kraus WE, Shah SH. Metabolic dysfunction in heart failure: diagnostic, prognostic, and pathophysiologic insights from metabolomic profiling. Curr Heart Fail Rep. 2016; 13:119–131.
Article
107. Wang P, Xu L, Sun A. Energy remodeling, mitochondrial disorder and heart failure. Curr Pharm Des. 2016; 22:4823–4829.
Article
108. Ruiz-Canela M, Toledo E, Clish CB, Hruby A, Liang L, Salas-Salvado J, et al. Plasma branched-chain amino acids and incident cardiovascular disease in the PREDIMED trial. Clin Chem. 2016; 62:582–592.
Article
109. Mirmiran P, Teymoori F, Asghari G, Azizi F. Dietary intakes of branched chain amino acids and the incidence of hypertension: a population-based prospective cohort study. Arch Iran Med. 2019; 22:182–188.
110. Du X, Li Y, Wang Y, You H, Hui P, Zheng Y, et al. Increased branched-chain amino acid levels are associated with long-term adverse cardiovascular events in patients with STEMI and acute heart failure. Life Sci. 2018; 209:167–172.
Article
111. Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation. 2016; 133:2038–2049.
Article
112. Wang W, Zhang F, Xia Y, Zhao S, Yan W, Wang H, et al. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol. 2016; 311:H1160–H1169.
Article
113. Li T, Zhang Z, Kolwicz SC Jr, Abell L, Roe ND, Kim M, et al. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metab. 2017; 25:374–385.
Article
114. Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci. 2015; 137:20–27.
Article
115. Fernstrom JD. Large neutral amino acids: dietary effects on brain neurochemistry and function. Amino Acids. 2013; 45:419–430.
Article
116. Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005; 135(6 Suppl):1539S–1546S.
Article
117. Pardridge WM. Kinetics of competitive inhibition of neutral amino acid transport across the blood-brain barrier. J Neurochem. 1977; 28:103–108.
Article
118. Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimers Dis. 2017; 57:1041–1048.
Article
119. Ono H, Pocai A, Wang Y, Sakoda H, Asano T, Backer JM, et al. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest. 2008; 118:2959–2968.
Article
120. Lee HK, Kwon B, Lemere CA, de la Monte S, Itamura K, Ha AY, et al. mTORC2 (Rictor) in Alzheimer's disease and reversal of amyloid-β expression-induced insulin resistance and toxicity in rat primary cortical neurons. J Alzheimers Dis. 2017; 56:1015–1036.
Article
121. Hudd F, Shiel A, Harris M, Bowdler P, McCann B, Tsivos D, et al. Novel blood biomarkers that correlate with cognitive performance and hippocampal volumetry: potential for early diagnosis of Alzheimer's disease. J Alzheimers Dis. 2019; 67:931–947.
Article
122. Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL. Metabolite profiling for the identification of altered metabolic pathways in Alzheimer's disease. J Pharm Biomed Anal. 2015; 107:75–81.
123. Tynkkynen J, Chouraki V, van der Lee SJ, Hernesniemi J, Yang Q, Li S, et al. Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: a prospective study in eight cohorts. Alzheimers Dement. 2018; 14:723–733.
Article
124. Larsson SC, Markus HS. Branched-chain amino acids and Alzheimer's disease: a Mendelian randomization analysis. Sci Rep. 2017; 7:13604.
Article
125. Ruiz HH, Chi T, Shin AC, Lindtner C, Hsieh W, Ehrlich M, et al. Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimers Dement. 2016; 12:851–861.
Article
126. Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006; 7:940–946.
127. Knight EM, Ruiz HH, Kim SH, Harte JC, Hsieh W, Glabe C, et al. Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer's APP/PSEN1 mice by gene targeting of diabetes/Alzheimer's-related Sorcs1. Acta Neuropathol Commun. 2016; 4:16.
Article
128. Li H, Ye D, Xie W, Hua F, Yang Y, Wu J, et al. Defect of branched-chain amino acid metabolism promotes the development of Alzheimer's disease by targeting the mTOR signaling. Biosci Rep. 2018; 38:BSR20180127.
Article
129. Tournissac M, Vandal M, Tremblay C, Bourassa P, Vancassel S, Emond V, et al. Dietary intake of branched-chain amino acids in a mouse model of Alzheimer's disease: effects on survival, behavior, and neuropathology. Alzheimers Dement (N Y). 2018; 4:677–687.
Article
130. Parrella E, Maxim T, Maialetti F, Zhang L, Wan J, Wei M, et al. Protein restriction cycles reduce IGF-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer's disease mouse model. Aging Cell. 2013; 12:257–268.
Article
131. Du Y, Meng Q, Zhang Q, Guo F. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT. Amino Acids. 2012; 43:725–734.
Article
132. Yan LJ, Thangthaeng N, Sumien N, Forster MJ. Serum dihydrolipoamide dehydrogenase is a labile enzyme. J Biochem Pharmacol Res. 2013; 1:30–42.
133. Vaubel RA, Rustin P, Isaya G. Mutations in the dimer interface of dihydrolipoamide dehydrogenase promote site-specific oxidative damages in yeast and human cells. J Biol Chem. 2011; 286:40232–40245.
Article
134. Klivenyi P, Starkov AA, Calingasan NY, Gardian G, Browne SE, Yang L, et al. Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J Neurochem. 2004; 88:1352–1360.
Article
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