Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases

Abstract

Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation. The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency-especially in obesity and associated metabolic disorders-and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances. This study focuses on the importance of diet, gut microbiota, and liver metabolism in determining glycine availability in obesity and associated metabolic disorders.

Keywords: amino acid metabolism; gut–liver axis; nutritional prevention; pathophysiology of metabolic disorders.

Figure 1

Main dietary sources and metabolic pathways of glycine. (Enzymes with a quantitatively prominent significant physiological role are presented in gray). Note: AAO = D-amino acid oxidase; BHMT = betaine-homocysteine S-methyltransferase; CHDH = choline dehydrogenase; DHF = dihydrofolate; DHFR = dihydrofolate reductase; DMGDH = dimethylglycine dehydrogenase; GNMT = glycine N-methyltransferase; PHGDH = phosphoglycerate dehydrogenase; PSAT = phosphoserine aminotransferase; PSPH = phosphoserine phosphatase; SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine; SDH = sarcosine dehydrogenase; SHMT = serine hydroxymethyltransferase; THF = tetrahydrofolate; CH₂-THF = N⁵, N¹⁰-methylene tetrahydrofolate. Labels in blue evidence the obesity-associated alterations in the expression or activity of the main enzymes determining glycine availability (for details see text in Section 2). Dietary glycine availability and uptake by the organism is regulated by the microbiota and gut metabolism (for details, see text in Section 3).

Figure 2

Potential mechanisms contributing to systemic glycine deficiency during metabolic diseases associated with obesity. Glycine dietary intake may not be the main determinant of glycine availability for the organism. Interactions between the food matrix and the intestinal microbiota influence the bacterial composition and metabolic capacity of the latter, thus modifying its ability to use glycine and produce metabolites derived from glycine. Alterations in glycine availability or microbial metabolites can modulate the expression of genes in intestinal compartments and impact the ability of the intestinal epithelium to take up glycine. Finally, interactions between the host genetics and physiology and the amount of glycine driven through the portal vein determine the fate of glycine, its bioavailability for the whole body, and its consequences on the host metabolism.

Figure 3

Main pathways involving glycine in host metabolism. Note: ALAS = delta-aminolevulinic acid synthase; BHMT = betaine-homocysteine S-methyltransferase; CBS = cystathionine β-synthase; CGL = cystathionine γ-lyase; GNMT = glycine N-methyltransferase; GCL = glutamate–cysteine ligase; GS = glutathione synthase; MAT = methionine adenosyltransferase; MS = methionine synthase; SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine; SDH = sarcosine dehydrogenase; SHMT = serine hydroxymethyltransferase; THF = tetrahydrofolate; CH₂-THF = N⁵, N¹⁰-methylene tetrahydrofolate; 5-methyl-THF = 5-methyltetrahydrofolate.

Figure 4

Main pathways involving glycine in health benefits. Metabolic benefits mediated by glycine include the inhibition of oxidative stress via increased glutathione biosynthesis, an inhibitory effect on gluconeogenesis and food intake via activation of the NMDA receptor, curbing the overload. Glycine also exerts positive effects on mitochondrial activity via heme biosynthesis, detoxification processes via urinary excretion of glycine conjugates, and regulation of hormonal (enhanced secretion of key hormones in glucose homeostasis) and cytokine (reduced production of pro-inflammatory cytokines) responses via activation of GlyRs. Finally, glycine impinges the SAM biosynthetic process, decreasing the availability of methyl-donors, and thus regulating methylation. Favorable pathways induced by glycine are green; the harmful pathways inhibited by glycine are red. Note: NMDA = N-methyl-D-aspartate; GlyRs = glycine receptors; SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine.