Metabolic and Regulatory Roles of Leucine in Neural Cells

Abstract

Dietary leucine transported into the brain parenchyma serves several functions. Most prominent is the role of leucine as a metabolic precursor of fuel molecules, alpha-ketoisocaproate and ketone bodies. As alternatives to glucose, these compounds are forwarded by the producing astrocytes to the adjacent neural cells. Leucine furthermore participates in the maintenance of the nitrogen balance in the glutamate/glutamine cycle pertinent to the neurotransmitter glutamate. Leucine also serves as a regulator of the activity of some enzymes important for brain energy metabolism. Another role of leucine as an informational molecule is in mTOR signaling that participates in the regulation of food ingestion. The importance of leucine for brain function is stressed by the fact that inborn errors in its metabolism cause metabolic diseases often associated with neuropathological symptoms. In this overview, the current knowledge on the metabolic and regulatory roles of this essential amino acid in neural cells are briefly summarized.

Glial Metabolism of Isoleucine

“…[1,[2][3][4][5][6][7][8][9][10][11][12][13] C]acetyl-CoA entering the TCA cycle by citrate synthase gives rise to [4,[5][6][7][8][9][10][11][12][13] C]glutamine via [4,[5][6][7][8][9][10][11][12][13] C]2-oxoglutarate. If the latter remains in the cycle its carbon chain will be converted to the symmetrical molecules succinate and fumarate and subsequently will give rise to [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]malate and [3,4-13 C]malate as well as the corresponding isotopomers of oxaloacetate. These 13 Clabelled isotopomers of malate and oxaloacetate can be transformed under the influence of malic enzyme or phosphoenolpyruvate carboxykinase to [1,[2]…”

“…If the latter remains in the cycle its carbon chain will be converted to the symmetrical molecules succinate and fumarate and subsequently will give rise to [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]malate and [3,4-13 C]malate as well as the corresponding isotopomers of oxaloacetate. These 13 Clabelled isotopomers of malate and oxaloacetate can be transformed under the influence of malic enzyme or phosphoenolpyruvate carboxykinase to [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate or [3-13 C]pyruvate, thereby leaving the cycle and serving as precursors of the corresponding lactate isotopomers (Fig. 2a).…”

“…13 C of pyruvate may re-enter the cycle by successive actions of the pyruvate dehydrogenase complex and citrate synthase. Indeed, labelled spin-offs from the TCA cycle were identified as [1,[2][3][4][5][6][7][8][9][10][11][12][13] Fig. 5b; Table 2).…”

“…Besides other common functions they share features of their metabolism. BCAAs are easily transported through the blood-brain barrier into the brain parenchyma [1], where they fulfill several distinct tasks [2,3]: (1) As proteinogenic amino acids they are indispensable in protein synthesis; (2) together with their cognate branched-chain 2-oxo acids, BCAAs serve in maintaining the nitrogen balance in the glutamate/glutamine cycle [4,5]; (3) since, even in the presence of glucose, the BCAAs are rapidly degraded by brain slices [6], neuron-rich [7,8] and astroglia-rich primary cultures [7,9], they are considered as valuable fuel molecules in brain energy metabolism. Furthermore, degradation of BCAAs, especially leucine, provides carbon residues which enter the general metabolism of neural cells and thus are incorporated, e.g., into lipids [10,11] and amino acids [12,13].…”

Ketone ester effects on metabolism and transcription

“…In vitro, ketone body production has been observed during the metabolism of leucine in glial cells ( 7 ). However, the quantitative importance of this pathway has not been established in vivo.…”