Written by Michael J. Rudolph, Ph.D.
12 October 2021


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Leucine to Burn Fat and Build Muscle

Enhance Muscle ProteinSynthesis 33%


By Michael J. Rudolph, Ph.D.


A scientific study demonstrated that consumption of leucine immediately after exercise specifically enhances muscle protein synthesis by as much as 33%.


Building a lean, muscular body requires a seemingly unwinnable tug-of-war within the body that occurs between muscle-building anabolism and fat-depleting catabolism, as each process counteracts one another at what seems to be every turn. Indeed, the simultaneous loss of considerable body fat while adding muscle mass appears, at times, impossible. One principal reason being greater muscle mass requires abundant food consumption, which naturally inhibits the ability to simultaneously lose body fat. To the contrary, getting leaner typically requires caloric restriction, which tends to mitigate muscle growth.


At the molecular level, the discord between muscle growth and fat loss stems, in large part, from the key fat-burning enzymes AMPK and SIRT1, which directly neutralize the muscle-building enzyme mTOR – whereas an activated mTOR directly inhibits AMPK and SIRT1 function. More specifically, hypocaloric diets and caloric-burning cardiovascular training employed to get lean potently activate AMPK and SIRT1 while intense resistance training combined with a high-protein meal triggers mTOR function optimally, further demonstrating the elemental incompatibility of packing on muscle while reducing body fat.


Nutritional supplements also ostensibly fail to support concomitant fat loss and muscle growth because this class of compounds tends to activate either mTOR or the AMPK/SIRT1 axis, but never both. Well, except for the remarkable branched-chain amino acid (BCAA) leucine – which quite surprisingly has the unique capacity to independently stimulate mTOR or SIRT1 when consumed at different doses with higher leucine doses (approximately 5 grams per day), specifically triggering mTOR and lower leucine intake (1 to 2 grams per day) activating only SIRT1.


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Higher Leucine Dose Promotes mTOR-driven Muscle Growth


It has been well documented that doses of leucine around 2 to 4 grams, especially when combined with weight training, preferentially stimulates mTOR activity, which simultaneously increases muscle protein synthesis while reducing muscle protein breakdown – ultimately resulting in muscle protein accumulation which drives muscle growth. Many scientific studies have highlighted mTOR activation by leucine combined with resistance training, including a seminal study by Walker et al.1 where they showed intake of leucine shortly after working out increased mTOR activity, leading to greater post-workout muscle protein synthesis as compared to an exercised group that was not fed leucine. While a second scientific inquiry by Pasiakos et al.2 demonstrated that consumption of leucine immediately after exercise specifically enhances muscle protein synthesis by as much as 33%.


Lower Leucine Burns Fat For Energy


In contrast to mTOR activation by leucine, activation of SIRT1 from leucine ingestion occurs at a blood concentration of approximately 0.5 millimolar (mM)3,4,5, which can be achieved from oral ingestion of approximately 1 gram of leucine per dose. This amount of leucine optimally activates SIRT1 without mTOR activation. In fact, taking 1.1 grams of leucine twice a day resulted in the requisite 0.5 mM of leucine in the blood.6,7 Although activation of the catabolic enzyme SIRT1 from ingesting leucine is counterintuitive, it actually appears quite logical when considering more muscle mass brought on by higher doses of leucine intake would ultimately require greater levels of energy to feed this added muscle mass. Consequently, lower levels of leucine in the blood, immediately subsequent to higher levels of muscle-building leucine, may represent a signal of impending energy requirement turning on SIRT1-generated energy production to support the expected increase in energetic demand. This running hypothesis was put to the test in two independent investigations where Sun et al.8,9 showed that leucine does, indeed, promote energy production from fatty acid oxidation in isolated fat cells due to SIRT1 activation. This work also showed these isolated fat cells were able to supply energy to isolated muscle cells when incubated together in the same test tube, indicating proper dosing of leucine can also be employed for fat loss. 


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Synergistic Activation of SIRT1


Leucine intake at levels that support SIRT1 function also enhances the activating effect of the SIRT1 cofactor NAD+. This is caused by the direct binding of leucine to SIRT1, which improves the interaction between SIRT1 and NAD+, effectively enabling SIRT1 activation at lower levels of NAD+.3 Because NAD+ is biochemically unstable when ingested orally, supplementing with more stable NAD+ boosting molecules, like NMN (nicotinamide mononucleotide) or NR (nicotinamide riboside) is the best practice. Nutritional supplementation with NMN or NR should boost NAD+ levels augmenting SIRT1 activity, especially when co-ingested with the lighter dose of leucine at 1 gram. While NR intake, by itself, does increase intracellular NAD+ in mammalian cells, it has still not been reported to influence SIRT1 activity when taken alone. The reason for this may be that NR use alone does not produce NAD+ levels high enough for effective SIRT1 activation. Of course, this putative shortcoming of NR should be averted when co-ingested with leucine as leucine lowers the level of NAD+ necessary to promote SIRT1 function. In fact, this is exactly what was observed when low doses of NAD+ donors NMN and NR were taken along with leucine, resulting in greater SIRT1 activity and fatty acid oxidation by 30% to 100% in adipocyte and muscle cells.10 Although human trials investigating NR or NMN intake with leucine have not been done yet, the adipocyte and muscle cell-based studies previously mentioned strongly suggest leucine synergizes with NR or NMN to potently activate SIRT1 – providing hope that this combination will provide health benefits, including body fat loss, associated with robust SIRT1 activity.


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Resveratrol and Leucine Synergistically Burn Fat and Prime Muscle Growth


In addition to NAD+ enhancing SIRT1 function, the plant polyphenol resveratrol can also directly bind, and activate, SIRT1.11,6 Although resveratrol possesses remarkable health-enhancing effects, this compound has poor bioavailability in humans as it is rapidly metabolized and removed from the body. As a result of this low bioavailability, oral consumption of resveratrol generates blood levels that are too low for meaningful effect. In fact, two recent studies showed resveratrol had no effect on several SIRT1-dependent metabolic functions in human test subjects12 or on any cardiometabolic effects in another 12-week human trial.13


Since leucine and resveratrol both activate SIRT1, concurrent intake of the two compounds should result in greater activation of SIRT1, perhaps lowering the quantity of resveratrol required to exert metabolic effects, including greater fat loss – essentially usurping the inherently low bioavailability of resveratrol. This effect was shown in a study by Bruckbauer et al.4 where they investigated the influence leucine and resveratrol had on SIRT1 activation as well as fat loss by putting 30 obese mice into three different groups, with one group receiving a high amount of resveratrol (225 milligrams), the second receiving leucine (24 grams), and the third group receiving a considerably lower amount of resveratrol (12.5 milligrams) relative to group one combined with the same amount of leucine (24 grams) given to group two. The results showed that low-dosed resveratrol in combination with leucine had a considerably greater impact on SIRT1 activation, driving a higher level of fatty acid oxidation and fat loss when compared to leucine or resveratrol alone – ultimately supporting the notion that leucine intake enables resveratrol function in the body.


Of course, human studies still need to show the leucine-resveratrol combo works in humans. Interestingly, the mice fed resveratrol and leucine also had greater insulin sensitivity, suggesting a more efficient insulin-signaling cascade. Since insulin drives muscle protein synthesis, more effective insulin signaling will enhance capacity for muscle growth, indicating the combined use of resveratrol and leucine may also prime the body for superior muscle growth.


For most of Michael Rudolph’s career he has been engrossed in the exercise world as either an athlete (he played college football at Hofstra University), personal trainer or as a research scientist (he earned a B.Sc. in Exercise Science at Hofstra University and a Ph.D. in Biochemistry and Molecular Biology from Stony Brook University). After earning his Ph.D., Michael investigated the molecular biological effects of exercise as a fellow at Harvard Medical School and Columbia University. That research contributed seminally to understanding the function of the incredibly important cellular energy sensor AMPK – leading to numerous publications in peer-reviewed journals including the journal Nature. Michael is currently a Senior Scientist working at the New York Structural Biology Center where he investigates the molecular nature of human illness and disease.




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2. Pasiakos SM, McClung HL et al. Leucine-enriched essential amino acid supplementation during moderate steady state exercise enhances postexercise muscle protein synthesis. Am J Clin Nutr 94, 809-818.


3. Bruckbauer A and Zemel MB. Synergistic effects of polyphenols and methylxanthines with Leucine on AMPK/Sirtuin-mediated metabolism in muscle cells and adipocytes. PLoS One 9, e89166.


4. Bruckbauer A, Zemel MB et al. Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutr Metab (Lond) 9, 77.


5. Fu L, Bruckbauer A et al. Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice. Metabolism 64, 845-856.


6. Katsanos CS, Kobayashi H et al. A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 291, E381-387.


7. Matsumoto T, Nakamura K et al. Bolus ingestion of individual branched-chain amino acids alters plasma amino acid profiles in young healthy men. Springerplus 3, 35.


8. Sun X and Zemel MB. Leucine modulation of mitochondrial mass and oxygen consumption in skeletal muscle cells and adipocytes. Nutr Metab (Lond) 6, 26.


9. Sun X and Zemel MB. Leucine and calcium regulate fat metabolism and energy partitioning in murine adipocytes and muscle cells. Lipids 42, 297-305.


10. Bruckbauer A and Zemel MB. Effects of dairy consumption on SIRT1 and mitochondrial biogenesis in adipocytes and muscle cells. Nutr Metab (Lond) 8, 91.


11. Borra MT, Smith BC and Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 280, 17187-17195.


12. Kantartzis K, Fritsche L et al. Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: A randomized, double-blind, placebo-controlled clinical trial. Diabetes Obes Metab 20, 1793-1797.


13. Asghari S, Asghari-Jafarabadi M et al. Comparison of Calorie-Restricted Diet and Resveratrol Supplementation on Anthropometric Indices, Metabolic Parameters, and Serum Sirtuin-1 Levels in Patients With Nonalcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial J Am Coll Nutr 37, 223-233.



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