Leucine represents a significant branched-chain amino acid essential for protein synthesis within human physiology. Recent scientific interest has grown around this particular amino acid due to its capability to enhance muscular development while positively influencing both glucose tolerance and sensitivity to insulin. Furthermore, research indicates that leucine impacts the metabolism of lipids and energy both inside organisms and in laboratory settings, potentially contributing to obesity reduction. This review examines leucine's physiological functions and its involvement in energy metabolism among mammals, with particular emphasis on its ability to stimulate muscle formation and facilitate fat breakdown. The information provided offers valuable insights for addressing various conditions including metabolic disorders, muscle wasting, and neurological pathologies, while also suggesting practical applications across food production industries and livestock management practices.
Leucine's Role in Metabolism
Leucine has a strong oxidative capacity, and its main physiological functions include regulating protein metabolism and the supply of oxidative energy. This energy supply can be used in special physiological periods, such as hunger, lactation, and exercise, as well as regulating immune function and lipid metabolism. Leucine can also be directly broken down into acetyl-CoA, making it one of the most important ketogenic amino acids in the body (using fat to produce ketone bodies when glucose cannot provide energy), which can directly or indirectly promote protein synthesis by increasing blood insulin levels, and can inhibit the breakdown of skeletal muscle protein.
Leucine Absorption and Distribution
Leucine enters cells via active transport mechanisms, including Na+-dependent diffusion, efflux, and heterologous exchange. It enters the central nervous system primarily through the blood-brain barrier and enters muscle and other tissues via specific transporters such as LAT1 .
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Leucine catabolism
Leucine can be broken down in the body through a variety of pathways. The main decomposition pathways include :
Decarbohydrate metabolism : Two processes are involved. Initially, ingested leucine is catalyzed by branched-chain amino acid transferase (BCAT) to produce precursors of α-ketoisocaproate (KIC) and β-hydroxy-β-methylbutyrate (HMB); this transamination is rapid and bidirectional. Subsequently, KIC enters one of two metabolic pathways to produce isovaleryl-CoA (accounting for 90-95% of leucine metabolism) or HMB (accounting for 5-10% of leucine metabolism). In the latter, α-ketoisocaproate is irreversibly metabolized to HMB by α-ketoisocaproate dioxygenase; in the former, α-ketoisocaproate undergoes irreversible and rate-limiting oxidative decarboxylation through a series of reactions catalyzed by branched-chain α-ketoacid dehydrogenase (BCKD). Ultimately, leucine is converted to acetoacetate and acetyl-CoA, which are intermediates of the tricarboxylic acid cycle. Excess α-ketoisocaproate can be released into the circulation and taken up by other organs such as the liver and adipose tissue, where it is then resynthesized into branched-chain amino acids or oxidized to produce adenosine triphosphate (ATP).
Figure 1. Leucine metabolism pathways.
Fatty acid synthesis: The metabolites of leucine, acetyl-CoA and acetoacetate, can further participate in the synthesis of fatty acids .
Energy metabolism: HMB, a metabolite of leucine, has antioxidant properties that can promote protein synthesis and reduce muscle breakdown .
Leucine metabolites influence energy homeostasis regulation
Leucine and its metabolites are hypothesized to be regulatory signals for energy homeostasis. Studies have shown that leucine metabolites rather than leucine itself may be the signal for mTOR activation. mTOR, the mammalian target of rapamycin, is an important regulator of cell growth and proliferation. In addition to leucine, β-hydroxy-β-methylbutyrate and α-ketoisocaproate are direct activators of the silent information transcription regulator 1 (SIRT1) enzyme. It is clear that leucine plays a key role in the allocation of energy from adipose tissue to skeletal muscle, resulting in a decrease in energy storage in adipocytes and an increase in fatty acid utilization in muscle.
α-Ketoisocaproic acid (KIC)
Existing literature shows that KIC is more effective than leucine in activating mTOR signaling and SIRT1. Both KIC and leucine inhibit lipid anabolism in adipocytes while promoting fatty acid oxidation (FAO).
Furthermore, KIC treatment increased oxidation of branched-chain amino acids in cultured C2C12 myotubes. KIC increases intact fatty acid oxidation in skeletal muscle by inhibiting BCKD kinase, leading to robust activation of the BCKD complex and increased flux through the branched-chain amino acid oxidation pathway.
Increased free fatty acid oxidation reduces glucose utilization, while increased muscle mass can effectively enhance fat oxidation. However, it is worth noting that KIC may be a double-edged sword, which, while promoting growth, increases fatty acid synthesis by downregulating the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), thereby negatively affecting lipid metabolism in adipose tissue.
β-Hydroxy-β-methylbutyrate (HMB)
In vitro and in vivo evidence suggests that the endogenous conversion of leucine to HMB is approximately 5–10% efficient. Nevertheless, the effects of HMB as a dietary supplement have been the focus of recent lipid metabolism research.
HMB is an interesting sports supplement. In human trials, HMB intake during endurance training has a favorable effect on reducing fat mass. As athletes try to maintain a certain body weight (mainly by reducing the amount of adipose tissue), HMB supply may be a suitable option for them and can have a positive impact on their physical performance. In a particularly interesting study, diet-induced obese mice were treated with low-dose (2g/kg diet) or high-dose (10g/kg diet) HMB for 6 weeks, which resulted in increased adipose SIRT1 activity, increased muscle glucose uptake and palmitate uptake, insulin sensitivity, and improvements in inflammatory stress biomarkers and reduced adiposity.
Dietary HMB supplementation modulates adipose tissue function, including fatty acid and lipolysis, while increasing serum adiponectin concentrations. These effects may be mediated in part by the AMPKa-mTOR pathway, and are associated with mitochondrial biogenesis, the AMPK-SIRT1-proliferator-activated receptor gamma coactivator-1a (PGC-1a) axis, and myokines.
Notably, HMB also plays a key role in regulating mitochondrial function, which has been implicated in many diseases such as aging, neurodegenerative disorders, obesity, diabetes, and cardiovascular disease.
Treatment of myotubes with a dose of HMB (50 mM) for 24 h significantly increased mitochondrial mass, respiratory capacity, and biogenesis, and was superior to the effects observed with leucine treatment.
Lipid Metabolism and Leucine
Leucine can reduce the activity of proteins related to fatty acid transport and synthesis, and inhibit the synthesis of fatty acids. It can regulate the expression of related signal factors and stimulate the secretion of glucagon-like peptide, thereby promoting lipolysis.
Leucine promotes fat metabolism
- Leucine helps break down fat and reduce obesity
It has been reported that leucine can inhibit adipogenesis, promote lipolysis and fatty acid synthesis, and significantly increase leptin secretion in adipocytes through the mTOR signaling pathway, which is beneficial for reducing obesity.
Increased leucine during adipocyte differentiation reduces levels of lipid droplet coat proteins surrounding lipid droplets, increases phosphorylation of hormone-sensitive lipase, and promotes lipolysis.
- Leucine may reduce diabetes risk
Dietary leucine can reduce high blood sugar and high cholesterol caused by a high-fat diet, reduce body fat and fat production rate, and increase insulin sensitivity.
Studies have found that supplementing with leucine can significantly improve glucose tolerance and show a good dose-effect relationship. At the same time, leucine can inhibit the rise in blood sugar after consuming starch and effectively inhibit the increase in blood sugar after a meal. Its mechanism is closely related to the promotion of gastrointestinal hormone glucagon-like peptide-1 (GLP-1).
GLP-1 has the function of regulating insulin release and glucose metabolism. When leucine is supplemented, a large amount of glucose is stored in the liver and muscles in the form of glycogen, effectively reducing the glucose concentration in the blood. It is effective in treating dizziness. Both type 1 and type 2 diabetics can benefit from a leucine-rich diet that minimizes carbohydrate intake.
- Leucine may reduce cardiovascular disease risk
Furthermore, the researchers concluded that dietary leucine metabolites in humans lead to lower triglycerides and LDL cholesterol, thereby improving cardiovascular function. In athletes, 4 weeks of resistance training with HMB supplementation significantly reduced cardiovascular risk factors such as low-density lipoprotein or total cholesterol and triglycerides.
Recently, some researchers have emphasized that leucine oxidation may be required for the activation of mTOR, a cytosolic serine/threonine protein kinase that appears to mediate fatty acid oxidation, so leucine may regulate adipose tissue metabolism through KIC or HMB and act as a nutrient sensor. The energy supply of fatty acid oxidation in adipose tissue is mainly used for protein turnover in muscle tissue, which is one of the reasons why leucine reduces fat deposition and reduces weight, but the exact mechanism behind these phenomena needs further study.
Leucine promotes browning
Leucine may promote browning and mitochondrial biogenesis in white adipose tissue (WAT) through the SIRT1-AMPK-PGC-1α axis.
- Leucine improves metabolic health by promoting browning of adipose tissue
Adipose tissue plays an important role in regulating whole-body energy metabolism through energy storage in white adipocytes and energy expenditure in brown adipocytes. Indeed, the accumulation of excess white adipose tissue can have deleterious effects on metabolic health, whereas activation of brown adipose tissue helps balance blood glucose levels and increases energy expenditure, thus having beneficial effects on obesity, insulin resistance, and hyperlipidemia.
Leucine is known to be essential for brown adipocyte differentiation. Therefore, in stimulating the development of white adipocytes in white adipose tissue, "browning" may reduce the adverse effects of white adipose tissue and may help improve metabolic health.
- Leucine may affect adipose tissue via gut microbes
Recently, the gut microbiota has been shown to regulate the browning of white adipose tissue and the activity of brown adipose tissue; this activity can be modulated by leucine. Leucine supplementation has been shown to induce a nearly fourfold increase in the mRNA expression of uncoupling protein 1 (UCP-1), a brown fat-specific gene, in white adipose tissue.
Leucine regulates lipid metabolism via mitochondria
There is increasing evidence that mitochondria may play a key role in regulating lipid metabolism in adipocytes. Specifically, mitochondria are required for substrate oxidation and ATP generation, which provides energy for cellular function. Furthermore, increased mitochondrial abundance induced by overexpression of nuclear factor-erythroid 2-related factor 2 in adipose tissue increases adiponectin synthesis and has been shown to stimulate fatty acid oxidation.
Note: Nuclear factor-erythroid 2-related factor 2 is an important molecule in regulating the expression of anti-inflammatory, anti-apoptotic and antioxidant genes in cells.
- Leucine regulates signaling pathways in adipocytes
In adipose tissue, the mTOR pathway appears to play an important role in preadipocyte differentiation, adipose tissue morphogenesis, hypertrophic growth, and leptin secretion. Freshly isolated adipocytes contain a leucine-stimulated recognition site that couples to mTOR signaling and regulates lipid metabolism in other aspects of mammalian physiology, including satiety, insulin secretion, and mitochondrial biogenesis.
This activity is largely due to the activation of the mTORC1 protein kinase, a master growth controller, which is regulated by the leucine sensor Sestrin2, an interacting protein that inhibits mTORC1 signaling. In fact, leucine modulates the mTOR signaling pathway in adipocytes both in vitro and in vivo, and does so more effectively than other amino acids.
- Leucine promotes mitochondrial biogenesis and thus regulates lipid metabolism
In addition, mTOR balances energy metabolism by controlling the oxidative function of mitochondria in a manner independent of protein kinase B. BCAT activates the mTOR signaling pathway, promotes mitochondrial biogenesis and ATP production, and defends against oxidative stress by regulating the expression of related genes. In other words, leucine promotes mitochondrial biogenesis, thereby regulating lipid metabolism.
Figure 2. Effects of dietary leucine on lipid metabolism in adipose tissue. (Zhang, L., et al., 2020)
Muscle Metabolism and Leucine
Skeletal muscle is the major site for glucose and fatty acid utilization and one of the main tissues contributing to insulin resistance in obesity and type 2 diabetes. Skeletal muscle plays a crucial role in energy homeostasis by clearing serum free fatty acids, systemic fatty acids, and lipid utilization.
Promotes muscle protein synthesis
The body uses amino acids to build muscle. This process is called muscle protein synthesis (MPS) and is essential for repairing muscle fibers damaged by physical stress caused by exercise, injury and aging. Leucine is one of the essential amino acids in the protein synthesis process, but can be used as an energy source during special physiological periods (hunger, lactation, stress and exercise, etc.). Because protein synthesis and protein degradation occur continuously, muscle protein is in a constant state of renewal. The "anabolic state" refers to a net gain in muscle protein. In contrast, the "catabolic state" refers to a net loss of muscle protein. Muscle protein is composed of twenty amino acids, all of which are required for the synthesis of new muscle protein. Nine of these amino acids must be obtained through dietary protein sources. Branched-chain amino acids are three of the nine essential amino acids and are very important for muscle protein metabolism. Leucine, in particular, is considered an important mediator of protein metabolism.
Leucine is uniquely shown to enhance athletic performance by stimulating muscle protein synthesis. Studies have found that leucine signals insulin, ultimately leading to greater activation of pathways that promote protein synthesis and prevent muscle breakdown.
Figure 3. Pathways of BCAA catabolism in skeletal muscle. (Holeček M., 2021)
Leucine affects skeletal muscle energy metabolism
Leucine is the only amino acid that can regulate protein turnover in skeletal muscle and myocardium. It can regulate the utilization of nitrogen in the body, thereby promoting the synthesis of protein in the body, promoting the secretion of insulin, inhibiting the secretion of glucagon, thereby inhibiting gluconeogenesis and slowing down the decomposition of muscle protein.
Leucine increases protein synthesis by up to 50% and inhibits breakdown by 25%. Leucine inhibits breakdown mainly by promoting insulin secretion through α-KIC, thereby inhibiting gluconeogenesis and slowing down muscle protein breakdown.
Leucine metabolites α-KIC and HMB also have the function of regulating protein metabolism. In addition, HMB, as a metabolite of leucine, also has the function of relieving fatigue.
Leucine promotes energy distribution to muscle cells
Its main metabolic site is in the muscle. Under the action of transaminase, leucine transfers the amino group to ketoglutarate to produce glutamate, and glutamate transfers the amino group to pyruvate to produce alanine.
Leucine regulates energy metabolism by modulating mitochondrial biogenesis and promotes fatty acid oxidation and mitochondrial biogenesis. Leucine promotes the allocation of energy from adipocytes to muscle cells, resulting in a decrease in lipid storage in adipocytes and an increase in fat utilization in muscle.
In addition, dietary leucine increases insulin sensitivity by promoting fatty acid synthesis in skeletal muscle. Leucine is shown to directly activate SIRT1 by promoting the affinity of the enzyme to its substrate and nicotinamide adenine dinucleotide (NAD)+, leading to increased mitochondrial biogenesis and fatty acid oxidation in adipocytes and muscles. Leucine also promotes the release of related hormones, such as growth hormone and IGF-1 (insulin-like growth factor-1), which are essential for the growth and development of children and adolescents.
Conclusion
As an important branched-chain amino acid, leucine plays a key role in energy metabolism, protein synthesis, lipid decomposition and muscle growth. Its metabolic pathway involves the mTOR signaling pathway, SIRT1 activation and AMPK regulation, which not only affects muscle growth and fat metabolism, but also has important significance for the regulation of glucose homeostasis, insulin sensitivity and obesity. In addition, leucine metabolites, such as KIC and HMB, show potential application value in maintaining energy balance, enhancing mitochondrial function and regulating inflammatory response. Further research on the leucine metabolic mechanism and its role in different physiological and pathological states will help develop nutritional intervention strategies for metabolic diseases, sarcopenia and neurodegenerative diseases, and also provide a scientific basis for the optimization of food science and animal husbandry.
References
- Zhang, L., Li, F., Guo, Q., Duan, Y., Wang, W., Zhong, Y., Yang, Y., & Yin, Y. (2020). Leucine Supplementation: A Novel Strategy for Modulating Lipid Metabolism and Energy Homeostasis. Nutrients, 12(5), 1299. https://doi.org/10.3390/nu12051299
- Holeček M. (2021). The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases. Physiological research, 70(3), 293–305. https://doi.org/10.33549/physiolres.934648
