Reviewing the Effects of l-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis
"> Figure 1
<p>Intracellular mechanisms activated by leucine. The mammalian target of rapamycin complex 1 (mTORC1) comprises mTOR, Raptor, mLST8, PRAS40, and DEPTOR. mTORC1 is activated by amino acids (especially leucine) as well as by hormones such as leptin, insulin, and IGF-1. mTORC1 can be activated by different pathways. Hormonal activation primarily occurs through the TSC complex. However, amino acid-dependent mTORC1 activation occurs through the Rag complex. The leucyl-tRNA synthetase is responsible for sensing leucine cellular levels and activating the Rag complex. The cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of leucine represent the rate-limiting step of mTOR activation. The protein p70-S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) are key downstream targets of mTORC1. S6K1 also phosphorylates components of the insulin signaling pathway, which may lead to insulin resistance in situations of nutrient abundance such as in obesity. The anorexigenic effects of leptin require both the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mTOR/S6K1 signaling pathways. Because mTOR is a downstream target of PI3K signaling, the acute anorexigenic effects of leptin may depend on the PI3K/mTOR/S6K1 pathway.</p> "> Figure 2
<p>Leucine-responsive tissues. After protein-rich meals, circulating BCAA levels significantly increase, whereas other amino acids are highly metabolized by the gut or liver before reaching the systemic circulation. Branched-chain amino acid transaminase (BCAT) catalyzes the first and reversible transamination step of leucine degradation. This enzyme is not expressed in the liver, which allows the BCAAs to bypass the portal venous system following their intestinal absorption. In the brain, leucine is metabolized by the cytosolic form of BCAT (BCATc), whereas in other tissues (e.g., white adipose tissue, skeletal muscle, and pancreas), the mitochondrial form of BCAT (BCATm) prevails.</p> "> Figure 3
<p>Neuronal circuitries required for the central effects of leucine on feeding. Central leucine administration (intracerebroventricular or parenchymal) acutely decreases food intake and body weight. This response is due to the activation of hypothalamic nuclei involved in regulating energy balance, including the paraventricular nucleus of the hypothalamus (PVH) and the arcuate nucleus of the hypothalamus (ARH), as well as extra-hypothalamic sites such as the nucleus of the solitary tract (NTS). Conversely, oral leucine administration does not induce neuronal activation in the PVH, ARH, or NTS but does cause c-Fos expression in the area postrema (AP). Consequently, no robust evidence indicates that oral leucine intake affects food intake. CVO, circumventricular organ; ME, median eminence.</p> "> Figure 4
<p>Possible effects of leucine supplementation in the regulation of energy balance and glucose homeostasis. This scheme summarizes the available evidence regarding the likely effects of leucine supplementation in different tissues and its subsequent consequences.</p> ">
Abstract
:1. Introduction
2. Intracellular Mechanisms Activated by Leucine
3. Leucine-Responsive Tissues
4. Central Effects of Leucine
5. Does Leucine Regulate Food Intake?
Reference | Route | Duration | Comments | Effects on Feeding |
---|---|---|---|---|
[40] | icv | Acute | - | Decreased |
[17] | icv | Acute | - | Decreased |
[43] | MBH | Acute/7 days | Food intake decreased in the first 2 days | Decreased |
[44] | NTS | Acute | - | Decreased |
[46] | icv | Acute | - | Decreased |
[47] | icv | Acute | - | Decreased |
Reference | Route | Duration | Comments | Effects on Feeding |
---|---|---|---|---|
[55] | Diet | 14 days | Normal and tumor-bearing pregnant rats | No changes |
[56] | Diet | Acute | Overnight food-deprived adult and old rats | No changes |
[57] | Diet | 20 days | Normal and tumor-bearing pregnant rats | No changes |
[58] | Diet | 12 days | Young and tumor-bearing pregnant rats | No changes |
[59] | Diet | 10 days | Adult and old rats | No changes |
[60] | Diet | 14 days | Leucine increased nocturnal meal size | No changes |
[61] | Diet | 9 weeks | Leucine + phenylalanine supplementation | No changes |
[62] | Diet | 7 days | - | No changes |
[17] | Diet | 3 weeks | Aversive behavior to leucine-rich diet in the 1°, but not in the 2° and 21° days. | Decreased |
[63] | Diet | 12 weeks | Healthy elderly men. Energy intake and macronutrient composition were calculated from dietary intake records. | No changes |
[64] | Diet | 8 weeks | Regular and high-fat diets | No changes |
[65] | Diet | 21 days | Lactating rats | No changes |
[66] | Diet | 5 weeks | - | No changes |
[67] | Diet | 24 weeks | Elderly type 2 diabetic men; 3 days’ dietary intake records to evaluate energy and macronutrient intake. | No changes |
[68] | Diet | 6 weeks | Previously obese rats | No changes |
[21] | Diet | 6 weeks | Regular and high-fat diets | No changes |
[50] | Diet | 7 days | HFD-fed mice; leucine produced similar effects as alanine supplementation. | Decreased |
[51] | Diet | 20 weeks | Mice consuming an HFD | Decreased |
[69] | Diet | 40 days | Old rats recovering from unilateral hind-limb casting | No changes |
[70] | Diet | 9 months | Aging rats | No changes |
[48] | Diet | 6 months | Increased food intake only in the first 2 weeks of supplementation | Increased/No changes |
[71] | Diet | 8 weeks | Rats consuming an HFD | No changes |
[46] | Diet | 4 days | Pronounced taste aversion | Decreased |
[49] | Diet | 24 weeks | Leucine increased food intake only in some points along the experiment | Increased/No changes |
[72] | Diet | 2 weeks | Nutritional recovery | No changes |
[73] | Diet | 40 days | Adult rats recovering from unilateral hind-limb casting | No changes |
[74] | Diet | 6 weeks | 30% calorie-restricted diet | No changes |
[75] | Diet | 27 weeks | - | No changes |
[47] | Diet | 12 days | - | No changes |
[76] | Diet | 8 weeks | Non-obese, insulin-resistant rats | No changes |
Reference | Route | Duration | Comments | Effects on Feeding |
---|---|---|---|---|
[27] | Water | 12 days | Leucine or norleucine supplementation | No changes |
[54] | Water | 14 weeks | Increased in chow diet group. No change in HFD group. | Increased/No changes |
[77] | Water | 14 weeks | Mice consuming an HFD | No changes |
[52] | Water | 8 weeks | Food intake decreased in RCS10 mice, but no changes were observed in yellow agouti mice. | Decreased/No changes |
[78] | Water | 8 weeks | Mice consuming an HFD | No changes |
[79] | Water | 10 weeks | Offspring from HFD-fed mothers | No changes |
[80] | Water | 8 weeks | Supplementation in normal and high-fat diets | No changes |
[81] | Water | 17 weeks | Mice consuming normal and high-fat diets | No changes |
[53] | Water | 9 weeks | Food intake decreased in males, but not females. No leucine effect in mice fed an HFD. | Decreased/No changes |
[46] | Water | 18 days | - | No changes |
[31] | Water | 6 weeks | Mice consuming normal and high-fat diets and ob/ob mice | No changes |
[38] | Water | 6 weeks | Rats consuming normal and high-fat diets | No changes |
[82] | Water | 21 weeks | Previously obese mice | No changes |
[46] | Gavage | 3 days | - | No changes |
[31] | Gavage | 2 days | - | No changes |
[83] | Gavage | 10 days | Supplementation during skeletal muscle recovery | No changes |
[46] | ip | 3 days | - | No changes |
[46] | sc | 3 days | - | No changes |
6. The Effects of Leucine on Body Composition, Obesity, and Energy Expenditure
7. Regulation of Glucose Homeostasis by Leucine
8. Concluding Remarks
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Pedroso, J.A.B.; Zampieri, T.T.; Donato, J., Jr. Reviewing the Effects of l-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis. Nutrients 2015, 7, 3914-3937. https://doi.org/10.3390/nu7053914
Pedroso JAB, Zampieri TT, Donato J Jr. Reviewing the Effects of l-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis. Nutrients. 2015; 7(5):3914-3937. https://doi.org/10.3390/nu7053914
Chicago/Turabian StylePedroso, João A.B., Thais T. Zampieri, and Jose Donato, Jr. 2015. "Reviewing the Effects of l-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis" Nutrients 7, no. 5: 3914-3937. https://doi.org/10.3390/nu7053914