Reviewing the Effects of L-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis

João A B Pedroso, Thais T Zampieri, Jose Donato Jr, João A B Pedroso, Thais T Zampieri, Jose Donato Jr

Abstract

Leucine is a well-known activator of the mammalian target of rapamycin (mTOR). Because mTOR signaling regulates several aspects of metabolism, the potential of leucine as a dietary supplement for treating obesity and diabetes mellitus has been investigated. The objective of the present review was to summarize and discuss the available evidence regarding the mechanisms and the effects of leucine supplementation on the regulation of food intake, energy balance, and glucose homeostasis. Based on the available evidence, we conclude that although central leucine injection decreases food intake, this effect is not well reproduced when leucine is provided as a dietary supplement. Consequently, no robust evidence indicates that oral leucine supplementation significantly affects food intake, although several studies have shown that leucine supplementation may help to decrease body adiposity in specific conditions. However, more studies are necessary to assess the effects of leucine supplementation in already-obese subjects. Finally, although several studies have found that leucine supplementation improves glucose homeostasis, the underlying mechanisms involved in these potential beneficial effects remain unknown and may be partially dependent on weight loss.

Keywords: branched-chain amino acids; central nervous system; diabetes mellitus; mTOR; obesity; protein synthesis.

Figures

Figure 1
Figure 1
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.
Figure 2
Figure 2
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.
Figure 3
Figure 3
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.
Figure 4
Figure 4
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.

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