Glutamine Metabolism in Macrophages: A Novel Target for Obesity/Type 2 Diabetes

Abstract

Obesity is a nutritional disorder resulting from a chronic imbalance between energy intake and expenditure. This disease is characterized by inflammation in multiple cell types, including macrophages. M1 macrophage responses are correlated with the progression of obesity or diabetes; therefore, strategies that induce repolarization of macrophages from an M1 to an M2 phenotype may be promising for the prevention of obesity- or diabetes-associated pathology. Glutamine (the most abundant amino acid in the plasma of humans and many other mammals including rats) is effective in inducing polarization of M2 macrophages through the glutamine-UDP-N-acetylglucosamine pathway and α-ketoglutarate produced via glutaminolysis, whereas succinate synthesized via glutamine-dependent anerplerosis or the γ-aminobutyric acid shunt promotes polarization of M1 macrophages. Interestingly, patients with obesity or diabetes show altered glutamine metabolism, including decreases in glutamine and α-ketoglutarate concentrations in serum but increases in succinate concentrations. Thus, manipulation of macrophage polarization through glutamine metabolism may provide a potential target for prevention of obesity- or diabetes-associated pathology.

Keywords: diabetes; glutamine; macrophages; obesity; succinate; α-ketoglutarate.

FIGURE 1

The relation between macrophages and obesity or diabetes. After activation of IRF/STAT-1 by stimulation with IFN-γ and LPS, macrophages convert to inflammatory macrophages (M1 macrophages), which are characterized by production of NO from arginine through iNOS activity, enhanced glycolysis, PPP flux, fatty acid synthesis, and impaired OXPHOS and TCA cycle activities. Anti-inflammatory macrophages (M2 macrophages, activation of IRF/STAT-6 with IL-4 stimulation) produce polyamines from arginine by arginase-1 and ornithine decarboxylase 1 and are characterized by OXPHOS, FAO, and less glycolysis and PPP. In lean adipose tissue, macrophages have an M2 phenotype and have critical roles in clearing cellular debris and lipid buffering, whereas macrophages in obese adipose tissue are M1 macrophages, which are activated by cytokines in the microenvironment of adipose tissues of obese individuals (1) and, in turn exacerbate inflammation in adipose tissue and trigger insulin resistance, as well as promote the development of metabolic syndrome associated with obesity (2). The blue pathway indicates activity in an impaired situation. FAO, fatty acid oxidation; iNOS, inducible NO synthase; IRF, interferon regulatory factor; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; STAT, signal transducer and activator of transcription; TCA, tricarboxylic acid.

FIGURE 2

Glutamine metabolism and macrophage polarization. In M1 macrophages, succinate accumulates due to glutamine-dependent anerplerosis and the GABA shunt. Succinate stabilizes HIF-1α through inhibiting the enzymatic activities of PHD or ROS, resulting in specific regulation of expression of IL-1β and other HIF-1α–dependent genes, including enzymes required for glycolysis. In M2 macrophages, α-ketoglutarate generated from glutaminolysis is essential for OXPHOS and FAO and promotes an M2 phenotype through Jmjd3 (a key enzyme for demethylation of H3K27)-dependent demethylation of H3K27 on the promoters of M2-specific marker genes, as well as inhibition of the activation of IKK through PHD, which inhibits the activation of IKKβ through hydroxylation of IKKβ on P191. Glutamine also supports M2 macrophage polarization through the glutamine–UDP-GlcNAc pathway. Also, M2 macrophages have a potential isocitrate to α-ketoglutarate conversion breakpoint in the metabolic flow of the TCA cycle. Pathways in black are enhanced in M1 macrophages, the pathways in blue are impaired, and pathways in red enhance differentiation of M2 macrophages. ABAT, 4-aminobutyrate aminotransferase; FAO, fatty acid oxidation; GABA, γ-aminobutyric acid; GlcNAc, glutamine–UDP-N-acetylglucosamine; GLS; glutaminase; GS, glutamine synthetase; HIF-1α, hypoxia inducible factor 1α; Idh1, isocitrate dehydrogenase 1; IKK, inhibitor of NF-κB kinase; Jmjd3, Jumonji domain-containing 3; KGDHC, α-ketoglutarate dehydrogenase complex; OXPHOS, oxidative phosphorylation; PHD, prolyl hydroxylase domain; ROS, reactive oxygen species; TCA, tricarboxylic acid.

FIGURE 3

Altered glutamine metabolism in adipose tissues from individuals with obesity or type 2 diabetes. (A) In adipose tissue from healthy subjects, which has fewer M2 macrophages, glutamine is catalyzed for generation of succinate through glutamine-dependent anerplerosis and GABA shunt. (B) In adipose tissue from obese individuals, which has more M1 macrophages, glutamine and α-ketoglutarate decrease (blue), whereas glutamate and succinate increase (red). Mechanistically, the abundance of glutaminase (an enzyme that converts glutamine to glutamate) increases (red), but the abundance of GS (an enzyme that converts glutamate to glutamine) and GPT (an enzyme that catalyzes the conversion of glutamate to α-ketoglutarate) decreases (blue). GABA, γ-aminobutyric acid; GLS, glutaminase; GPT, glutamate pyruvate transaminase; GS, glutamine synthetase; TCA, tricarboxylic acid.