By Steve Blechman

 A new study that was being presented at the 40^th European Society for Clinical Nutrition and Metabolism (ESPEN) Congress in Madrid, Spain on September 1-4, 2018 further confirms evidence that elevated branched-chain amino acids are associated with obesity.

 In my last article, I mentioned that branched-chain amino acids (BCAAs) had been identified in 2009 as a robust marker of obesity and insulin resistance in humans by Duke researchers led by Christopher Newgard, the director of the Duke Molecular Physiology Institute— according to ScienceDaily on May 17, 2018 and most recently published, in addition to findings by Duke University researchers in Cell Metabolism also on May 17, 2018. “The association between BCAA and insulin resistance had been present in the literature dating back to a 1969 study that appeared in the New England Journal of Medicine. And they have since been shown to be highly predictive of future diabetes development by the landmark Framingham Heart study,” the researchers concluded.

 This most recent study included 80 obese participants. High circulating BCAAs were negatively associated with free fatty acid concentrations. High blood levels of free fatty acids have been correlated in insulin resistance and type 2 diabetes (Diabetes, Obesity & Metab, June 2018). Elevated BCAA levels were significantly positively associated with deep visceral (abdominal fat) and hepatic (liver) fat. Liver fat content was assessed through magnetic resonance spectroscopy imaging (MRS), while visceral and subcutaneous adipose tissue were evaluated by magnetic resonance imaging (MRI). High visceral fat is strongly associated with the metabolic syndrome including inflammation, insulin resistance, diabetes, high triglycerides, high cholesterol, hypertension and fatty liver.

 A new study published in the most recent Journal of Physiology (August 2018) reported August 28, 2018 in ScienceDaily that according to a new study that obesity “…diminishes a person’s ability to build muscle after engaging in resistance exercise.” It was shown in the study that, “…the interactive effect of resistance exercise and feeding on the stimulation of myofibrillar protein synthesis rates is diminished with obesity when compared to normal weight adults.”

 Nicholas Burd, who was the head of the research team, said to ScienceDaily: “Our new study goes further, showing there is an obesity-related impairment in building new muscle proteins in the fed state after a weightlifting session.” Burd also goes on to tell the ScienceDaily news team, “The obese adults had plasma insulin concentrations that were approximately 3.2 times higher at baseline which highlights some level of whole-body insulin resistance.” Also, he said that, “We show that post-workout muscle building and repair is blunted in young adults with obesity. This is significant because muscle building and repair after exercise has long-term implications for metabolic health and overall physical performance.”

 It’s still not fully understood why obese individuals have elevated BCAAs and if elevated BCAAs increase the incidence of whole-body insulin resistance and diabetes. Research has shown that elevated levels of valine are present in the blood of diabetic rats, mice and humans (Nat Rev Endocrinol, 2014). It was reported in the journal Nature Medicine in 2015 that valine catabolite 3-hydroxyisobutyrate (3-HIB) promoted the accumulation of fat within muscle tissue by directly stimulating fatty uptake in the muscle. Scientists have discovered that 3-hydroxyisobutyrate (3-HIB), one of the intermediate products in the breakdown of the BCAA valine, plays a role in the transport of fatty acids into skeletal muscle cells, which creates fatty muscles— a contributor to insulin resistance. Could an increase in insulin resistance cause skeletal muscle breakdown and increase valine catabolite 3-HIB in the blood, and also increase abdominal (visceral) and liver fat as well as muscle fat? Is valine catabolite 3-HIB the metabolic culprit? Is that why high BCAAs are linked to obesity and diabetes?

 According to the Journal of Hepatology (Feb 2018), “Non-Alcoholic Fatty Liver Disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity.” In the United States alone, it affects an estimated 80-100 million people! NAFLD affects people who drink little or no alcohol and have enhanced storage of fat in the liver. NAFLD results in inflammation, scarring, liver damage, cirrhosis and liver cancer similar to the damage of heavy alcohol use, and is a leading cause of liver transplant worldwide. NAFLD is linked to metabolic syndrome related to abdominal fat storage, increased insulin resistance and elevated blood levels of triglycerides (a type of fat). Currently, there’s no approved pharmacologic or drug therapies for NAFLD or non-alcoholic steatohepatitis (NASH), which increases morbidity and mortality. Fat content in the liver can now be detected as well as liver inflammation, scarring, and damage by simple ultrasound and magnetic resonance imaging (MRI) (Science News, August 31, 2018, The Lancet/Diabetes and Endocrinology August 30, 2018.)

 Most recently, an editorial and feature article in the journal Aliment Pharamacol Ther. (August 2018) reported on the results of a randomized clinical trial for the potential effective treatment of non-alcoholic liver disease (NAFLD) with leucine in combination with metformin and sildenafil (also known as the brand drug Viagra™).

 “The concept of combining leucine, metformin and sildenafil (NS-0200) is novel and aims at augmenting the effect on a particular pathway, the 5’ adenosine monophosphate-activated protein kinase (AMPK)/Sirtuin 1 (SIRT 1) pathway.”

 Sirtuin-1 (SIRT1) is suppressed in non-alcoholic fatty liver disease (NAFLD). Leucine activates SIRT1 and synergizes with other SIRT1/AMPK/NO pathway activators. Leucine may also attenuate adiposity in the liver and promote weight loss during energy restriction (Nutrition, 2006, Diabetes, 2007). These effects are in part by activating the SIRT1-dependent pathway, stimulating mitochondrial biogenesis and increased oxygen consumption (Nutrition Metabolism, 2008). Mitochondrial biogenesis and SIRT1 expression in skeletal muscle has also been shown to increase lifespan in middle-aged mice (Cell Metabolism, 2010). A triple combination of leucine, metformin and sildenafil was used in the study, which has been found to be effective in animals. The study involved 91 subjects with NAFLD. It is a 16-week multicenter, randomized controlled trial in patients with NAFLD. The study found significantly reduced hepatic fat in NAFLD patients. The results of this study demonstrated the synergistic benefits of leucine with metformin and sildenafil in treatment of fatty liver disease.

 Another exciting new study published in Nutrition Research (September 2018) found that oral supplements of leucine upregulate slow-fiber mitochondria-related genes in skeletal muscle of rats. The human body produces two types of skeletal muscle fibers – slow-twitch (type 1) and fast-twitch (type 2). Endurance athletes have a greater proportion of slow-twitch fibers, whereas sprinters and jumpers have more of the fast-twitch fibers. Explosive powerlifting increases fast-twitch fibers while high-volume, lower-weight resistance training, (bodybuilding training/circuit training/bodyweight exercise) with little rest between sets, activates slow-twitch muscle fibers.

 Researchers found that acute oral administration of L-leucine alone could alter gene expression and fiber type in skeletal muscle of rats through activation of the mTOR pathway. Leucine also increased mitochondrial biogenesis-related gene (Ppargc1a.) Mitochondria are the “power centers of the cell.” Increasing the number of mitochondria results in mitochondrial biogenesis. This means the mitochondrial increase in volume and mass in your body resulting in greater production of ATP and energy expenditure. L-valine treatment did not alter the expression of fiber type or increase mitochondrial biogenesis.

 Another study from Victoria University in Melbourne, Australia found that beginning weight trainers given daily leucine supplements (4 grams per day for 12 weeks) gained more strength than those given a placebo (fake leucine). Supplemented subjects increased five-repetition maximum strength in eight exercises an average of 40.8 percent, while control subjects increased strength by 31 percent. People often have trouble adjusting to the early phases of weight training. Leucine supplements might help them recover faster and gain more strength. (International Journal Sports Physiology Performance, November 2011.)

 An article was published in ScienceDaily (August 2011) called “Research from Everest: Can leucine help burn fat and spare muscle tissue during exercise?” This study showed that leucine can help burn fat at high altitudes and preserve lean body mass. At the 242nd National Meeting and Exposition of the American Chemical Society on August 28, 2011, scientists studied 10 climbers for a period of six to eight weeks as they climbed Mount Everest. The climbers were given leucine as part of their diet.

 The article in ScienceDaily stated, “Wayne Askew, Ph.D. and his co-investigator, Stacie Wing-Gaia, Ph.D., who headed the leucine study, explained that the extreme weather conditions, low oxygen levels, treacherous terrain and strenuous exercise during such climbs create a huge nutritional challenge. Weight loss at high altitude is exactly the opposite problem that is on the minds of millions of people in the United States and other countries who are trying to shed excess weight. Climbers often cannot or do not eat enough calories, failing to replenish their bodies with important nutrients. They lose both fat and muscle during an arduous climb, endangering their strength and motor coordination. At high altitudes, fat and muscle loss occurs not only when they are climbing, but also at rest.”

 Dr. Askew also explained that, “The significant part about this weight loss is that a disproportionate amount comes from the muscle mass. This can be a problem on long expeditions at high altitude because the longer climbers are there and the higher they go, the weaker they get. The body breaks down the muscle for energy, so climbers don't have it available for moving up the mountain.”

 "We knew that leucine has been shown to help people on very low-calorie, or so-called 'calorie-restricted diets', stay healthy at sea level," said Askew. "It's one of the components, the building blocks, of protein. But no one had tested whether leucine would help people stay healthy and strong at high altitudes, so we added leucine to specially prepared food bars that we gave to the climbers.”

 Many people past 50 years of age have a condition called sarcopenia-a decline in skeletal muscle with aging. In a most recent study in the British Journal of Nutrition (August 28, 2018), it was found that in older adults with sarcopenia it was associated with reduced blood levels of the BCAA leucine. Older adults typically lose muscle mass with age because of loss of appetite and metabolic changes resulting in anabolic resistance that trigger muscle atrophy. Some of these changes include inflammation, insulin resistance and low testosterone output. Muscle loss, called sarcopenia, can interfere with quality of life and lead to life-threatening falls. Can increasing blood levels of leucine help prevent sarcopenia in the elderly?

  Increasing leucine in the diet may represent an effective intervention strategy for combating and reversing sarcopenia and functional decline in the aging (Nutrients, August 2018). A recent study published in the American Journal of Clinical Nutrition (February 2018) compared the effects of different amounts of leucine on hourly and daily muscle protein synthesis in healthy older women. “A 15-gram protein-containing beverage with ~ 4 grams of leucine induced greater increases in acute and integrated myoPS than did an isonitrogenous, isoenergetic mixed-protein beverage. Declines in muscle mass in older women may be attenuated with habitual, twice-daily consumption of a protein beverage providing 15 grams of protein and higher (4.2 g/serving) amounts of leucine.”

 An exciting new study looking at leucine and ACE inhibitors in sarcopenia (LACE)— a multicenter, masked, placebo-controlled, randomized trial— is evaluating the efficacy of leucine and perindopril (an angiotensin-converting enzyme inhibitor) in patients with sarcopenia. The trial is recruiting 440 patients, male and female, aged 70 years and over with sarcopenia. The results “will provide the first robust test of the overall clinical and cost-effectiveness of these novel therapies for older patients with sarcopenia,” researchers said. The intervention will be for one year. This randomized controlled trial will provide pure leucine, 2.5 grams, three times per day to participants or matching placebo (Trials, January 2018).

CAN LEUCINE PROTECT AGAINST CARDIOVASCULAR DISEASE?

 A recent study in the Journal Biofactors (February 15, 2018) it was shown that leucine might be protective of cardiovascular disease in humans by “…attenuating macrophage foam-cell formation by mechanisms related to the metabolism of cholesterol, triglycerides and energy production.” “Foam cells are a type of macrophage that localize to fatty deposits on blood vessel walls, where they ingest low-density lipoproteins and become laden with lipids, giving them a foamy appearance. These cells secrete various substances involved in plaque growth and their death promotes inflammation, thereby contributing to cardiovascular disease.” (Nature, https://www.nature.com/subjects/foam-cells.)

HOW TO TAKE LEUCINE FOR MAXIMIZING PROTEIN SYNTHESIS, MUSCLE GROWTH & RECOVERY

 As per my last article, for best results to use as an anabolic trigger, take 5 grams of leucine (on an empty stomach) 15-30 minutes before a post-workout meal. A meta-analysis (Nutrition, 2017) that combined the results of seven studies showed that BCAA supplements are best taken after exercise, not before, or during exercise (intra-workout).

 Leucine, not branched-chain amino acids (BCAAs), is the most important chemical that turns on the mTOR pathway, so it is likely that consuming leucine after exercise would be more effective (and cheaper) than consuming BCAAs. The BCAAs share the same active transport system into cells and muscle cells. Indeed, isoleucine and valine have been shown to inhibit absorption of leucine (Nutrition, 2017; Biochem J, 1966; Int J of Sp Nutr & Exer Metab, 2018).

 Robert R. Wolfe, noted amino acid researcher, states in the Journal of the International Society of Sports Nutrition (2017) that “BCAAs also compete with other amino acids for transport, including phenylalanine, and this competition could affect the intramuscular availability of other EAAs. As a result of competition for transporters, it is possible that leucine alone, for example, could have a transitory stimulatory effect on muscle protein synthesis where the BCAAs fail to elicit such response.”

 Timing of leucine ingestion is critical! By taking pure leucine on an empty stomach after your workout, you will get a better spike in blood levels than if you take leucine with food, because food can slow leucine’s absorption. The addition of isoleucine and valine may hinder the benefits of leucine due to competition for transport into muscle cells. When leucine is taken on an empty stomach, it’s a powerful metabolic switch that turns on protein synthesis.

 Leucine increases mTOR activity for several hours after training. Leucine should be taken on an empty stomach, after resistance exercise, and as an anabolic trigger before a post-workout, protein-containing meal (or protein shake) rich in essential amino acids. This will trigger greater protein synthesis for improved recovery and greater gains.

WHY LEUCINE IS STILL KING

 Leucine is an essential amino acid that serves as a building block for muscle protein synthesis. Leucine is a powerful anabolic trigger— it’s the most potent branched-chain amino acid (BCAA) and a key activator of the mTOR pathway that is critical for muscle protein synthesis that promotes muscle growth. Testosterone acts through the mTOR pathway to promote muscle protein synthesis. Leucine has many benefits: powering muscle growth, preventing muscle loss, increasing insulin sensitivity, enhancing fat metabolism and enhancing recovery.

 Bottom line: based on the latest scientific research, Leucine is still king, and the most potent anabolic/amino acid trigger! For added benefits, it is best taken with creatine monohydrate and betaine (found in AML PostWorkout™). Creatine stimulates muscle growth and recovery by increasing muscle cell formation and protein synthesis. Research has shown that creatine monohydrate combined with leucine can inhibit the production of wasting protein myostatin! Supplementing leucine post-exercise also enhances muscle creatine uptake via an insulin stimulated effect. Betaine is an excellent post-workout supplement when combined with leucine and creatine. “2.5 grams of betaine reduces fatigue and increased power and strength after 15 days of high-intensity, high-volume bench press and squat training. Betaine is also an osmolyte, enhancing muscle cell swelling, stimulating protein synthesis and decreasing protein breakdown, resulting in muscle growth. Betaine also has been shown to increase growth hormone and insulin-like growth factor 1 (IGF-1.)” (See my AML Article – Top 3 Post Workout Nutrients: Leucine, Creatine and Betaine.)

 There is no need to take supplements of BCAAs-isoleucine and valine that interfere with leucine and share the same active transport system into cells and muscle cells! Like I said earlier, isoleucine and valine have been shown to inhibit the absorption of leucine. Your diet and your post-workout meal will give you all the isoleucine, valine and other essential amino acids that you need!

References:

Poggiogalle E, Fontana M et al. Abstracts of the 40th ESPEN Congress, Madrid, Spain; September 1-4, 2018; European Society for Clinical Nutrition and Metabolism. OR45. Circulating Branched-Chain Amino Acids, Lipid Oxidation and Ectopic fat in Adults with Obesity.

Spiller S, Blüher M, Hoffmann R. Plasma levels of free fatty acids correlate with type 2 diabetes mellitus. Diabetes Obes Metab. June 2018;1-9. https://doi.org/10.1111/dom.13449

Konerman MA, Jones JC, Harrison SA. Pharmacotherapy for NASH: current and emerging. J Hepatol 2018;68:362-375.

Noureddin M and Loomba R (2018). Editorial: role of leucine‐metformin‐sildenafil combination in the treatment of nonalcoholic fatty liver disease (NAFLD). Aliment Pharmacol Ther, 48: 378-379. doi:10.1111/apt.14819.

Chalasani N, Vuppalanchi R et al. (2018) Randomized clinical trial: a leucine‐metformin‐sildenafil combination (NS‐0200) vs placebo in patients with non‐alcoholic fatty liver disease. Alimentary Pharmacology & Therapeutics, 47(12), 1639-1651. http://doi.org/10.1111/apt.14674

Marika Leenders, Luc JC van Loon. Leucine as a pharmaconutrient to prevent and treat sarcopenia and type 2 diabetes, Nutrition Reviews, Volume 69, Issue 11, 1 November 2011, Pages 675-689, https://doi.org/10.1111/j.1753-4887.2011.00443.x

Tessier AJ, Chevalier S. An Update on Protein, Leucine, Omega-3 Fatty Acids, and Vitamin D in the Prevention and Treatment of Sarcopenia and Functional Decline. Nutrients 2018, 10, 1099.

Devries M, McGlory C et al. Protein leucine content is a determinant of shorter- and longer-term muscle protein synthetic responses at rest and following resistance exercise in healthy older women: a randomized, controlled trial, The American Journal of Clinical Nutrition, Volume 107, Issue 2, 1 February 2018, Pages 217-226, https://doi.org/10.1093/ajcn/nqx028

Argyrakopoulou G, Kontrafouri P et al. The Effect of the Oral Administration of Leucine on Endothelial Function, Glucose and Insulin Concentrations in Healthy Subjects. Exp Clin Endocrinol Diabetes. DOI: 10.1055/a-0597-8985. March 2018.

Band MM, Sumukadas D et al. (2018) Leucine and ACE inhibitors as therapies for sarcopenia (LACE trial): study protocol for a randomised controlled trial. Trials, 19, 6. http://doi.org/10.1186/s13063-017-2390-9

Szmelcman S, Guggenheim K. Interference between leucine, isoleucine and valine during intestinal absorption. Biochemical Journal 1966;100(1):7-11.

Wolfe R. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? Journal of the International Society of Sports Nutrition 201714:30 https://doi.org/10.1186/s12970-017-0184-9.

Deldicque C, Sanchez C, Horman S. Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells. Amino Acids, 2008, Volume 35, Number 1, Page 147.

Hector A, Phillips S. Protein Recommendations for Weight Loss in Elite Athletes: A Focus on Body Composition and Performance. Int J Sport Nutr Exerc Metab 2017.

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, nxy091, June 13, 2018.

Rahimi MH, Shab-Bidar S et al. Branched-chain amino acid supplementation and exercise-induced muscle damage in exercise recovery: A meta-analysis of randomized clinical trials. Nutrition 2017.

American Chemical Society. Research from Everest: Can leucine help burn fat and spare muscle tissue during exercise? ScienceDaily, 28 August 2011. www.sciencedaily.com/releases/2011/08/110828171215.htm

American Chemical Society News Releases, 2011 August, Research from Everest: Can leucine help burn fat and spare muscle tissue during exercise? https://www.acs.org/content/acs/en/pressroom/newsreleases/2011/august/research-from-everest-can-leucine-help-burn-fat-and-spare-muscle-tissue-during-exercise.html

Robinson SM, Al-Daghri N et al. Does nutrition play a role in the prevention and management of sarcopenia? Clinical Nutrition, Volume 37, Issue 4, 1121-1132.

Liang C, Curry B et al. Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes. Journal of Nutrition and Metabolism, vol. 2014, Article ID 239750, 11 pages, 2014. https://doi.org/10.1155/2014/239750.

Lydia-Ann LS, Harris G et al. Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion-Induced Insulin Resistance Diabetes 2017;66:1871-1878. https://doi.org/10.2337/db16-1475

Mardinoglu, Adil et al. Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes, EBioMedicine, Volume 27, 151-155, Jan 2018.

Andersson-Hall U, Gustavsson C et al. 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, vol. 2018, Article ID 4207067, 12 pages, 2018. https://doi.org/10.1155/2018/4207067.

Cummings NE, Williams EM et al. (2018) Restoration of metabolic health by decreased consumption of branched‐chain amino acids. J Physiol 596: 623-645. doi:10.1113/JP275075

Duke University. Diabetes researchers find switch for fatty liver disease: Carbs, fats and protein: One molecule to rule them all? ScienceDaily, 17 May 2018. www.sciencedaily.com/releases/2018/05/180517113847.htm

Hiroyuki Kato, Katsuya Suzuki, Makoto Bannai, Daniel R Moore; Branched-Chain Amino Acids Are the Primary Limiting Amino Acids in the Diets of Endurance-Trained Men after a Bout of Prolonged Exercise, The Journal of Nutrition, Volume 148, Issue 6, 1 June 2018, Pages 925–931, https://doi.org/10.1093/jn/nxy048

ISSN exercise & sports nutrition review update: research & recommendations. Chad M. Kerksick Colin D. Wilborn, Michael D. Roberts, et al. Journal of the International Society of Sports Nutrition 2018 15:38 https://doi.org/10.1186/s12970-018-0242-y 1 June 2018

Nature, https://www.nature.com/subjects/foam-cells

Dreyer HC, Drummond MJ, Pennings B, Fujita S, Glynn EL, Chinkes DL, Dhanani S, Volpi E, Rasmussen BB. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mtor signaling and protein synthesis in human muscle. Am J Physiol Endocrinol & Metab. 2008;294(2):E392–400

Drummond MJ, Rasmussen BB. Leucine-enriched nutrients and the regulation of mammalian target of rapamycin signalling and human skeletal muscle protein synthesis. Curr Opin Clin Nutr Metab Care. 2008;11(3):222–6.

Mitchell, C. J., Churchward-Venne, T. A., West, D. W. D., Burd, N. A., Breen, L., Baker, S. K., & Phillips, S. M. (2012). Resistance exercise load does not determine training-mediated hypertrophic gains in young men. Journal of Applied Physiology, 113(1), 71–77. http://doi.org/10.1152/japplphysiol.00307.2012

Beals, J. W., Skinner, S. K., McKenna, C. F., Poozhikunnel, E. G., Farooqi, S. A., Vliet, S. , Martinez, I. G., Ulanov, A. V., Li, Z. , Paluska, S. A. and Burd, N. A. (2018), Altered anabolic signaling and reduced stimulation of myofibrillar protein synthesis after feeding and resistance exercise in people with obesity. J Physiol. Accepted Author Manuscript. . doi:10.1113/JP276210

University of Illinois at Urbana-Champaign. "Post-workout muscle building and repair blunted in obese adults." ScienceDaily. ScienceDaily, 28 August 2018. <www.sciencedaily.com/releases/2018/08/180828103951.htm>

Grajeda‐Iglesias, C. , Rom, O. , Hamoud, S. , Volkova, N. , Hayek, T. , Abu‐Saleh, N. and Aviram, M. (2018), Leucine supplementation attenuates macrophage foam‐cell formation: Studies in humans, mice, and cultured macrophages. BioFactors, 44: 245-262. doi:10.1002/biof.1415

Top 3 Post Workout Nutirients: Leucine, Creatine and Betaine https://advancedmolecularlabs.com/blogs/news/top-3-post-workout-nutrients-leucine-creatine-and-betaine