Immunomodulatory role of branched-chain amino acids

Bonvini, Andrea; Coqueiro, Audrey Yule; Tirapegui, Júlio; Calder, Philip C.; Rogero, Marcelo Macedo

doi:10.1093/nutrit/nuy037

Cited by 49 publications

(30 citation statements)

References 209 publications

(160 reference statements)

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“…Overall, tracer studies are consistent with glutamine use as an anaplerotic substrate when GLUT1 is absent. Of note, succinate enrichment was significantly reduced in Slc2a1 M2/2 BMDMs compared with controls, which could be explained by unlabeled anaplerotic substrates such as branched-chain amino acids entering at succinate through succinyl-CoA (77). Thus, further study of glutamine and branched-chain amino acid transport and metabolism with respect to GLUT1 deletion or inhibition should be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

Freemerman

Zhao

Pingili

et al. 2019

The Journal of Immunology

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Macrophages (MFs) are heterogeneous and metabolically flexible, with metabolism strongly affecting immune activation. A classic response to proinflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, whereas alternative activation is primarily oxidative, which begs the question of whether targeting glucose metabolism is a viable approach to control MF activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow-derived MFs (BMDM) from Slc2a1 M2/2 mice failed to uptake glucose and demonstrated reduced glycolysis and pentose phosphate pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MF lacking GLUT1, demonstrating an incomplete metabolic reprogramming. Slc2a1 M2/2 BMDMs displayed a mixed inflammatory phenotype with reductions of the classically activated pro-and anti-inflammatory markers, yet less oxidative stress. Slc2a1 M2/2 BMDMs had reduced proinflammatory metabolites, whereas metabolites indicative of alternative activation-such as ornithine and polyamines-were greatly elevated in the absence of GLUT1. Adipose tissue MFs of lean Slc2a1 M2/2 mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr 2/2 mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1 M2/2 BMDMs may have contributed to unstable atheroma formation. Together, our findings suggest that although lack of GLUT1 blunted glycolysis and the pentose phosphate pathway, MF were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated, yet phagocytic defects hindered MF function in chronic diseases.

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Section: Discussionmentioning

confidence: 99%

Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

Freemerman

Zhao

Pingili

et al. 2019

The Journal of Immunology

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“…Leucine, a branched-chain amino acid, can induce both anti-inflammatory and pro-inflammatory effects, probably depending on its circulating concentration [ 8 – 12 ]. Previous studies showed that the recommended amount of protein intake for older adults should be 1.0–1.5 g of proteins per kilogram body weight per day [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Thirteen weeks of supplementation of vitamin D and leucine-enriched whey protein nutritional supplement attenuates chronic low-grade inflammation in sarcopenic older adults: the PROVIDE study

et al. 2019

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Background A chronic low-grade inflammatory profile (CLIP) is associated with sarcopenia in older adults. Protein and Vitamin (Vit)D have immune-modulatory potential, but evidence for effects of nutritional supplementation on CLIP is limited. Aim To investigate whether 13 weeks of nutritional supplementation of VitD and leucine-enriched whey protein affected CLIP in subjects enrolled in the PROVIDE-study, as a secondary analysis. Methods Sarcopenic adults (low skeletal muscle mass) aged ≥ 65 years with mobility limitations (Short Physical Performance Battery 4–9) and a body mass index of 20–30 kg/m 2 were randomly allocated to two daily servings of active ( n = 137, including 20 g of whey protein, 3 g of leucine and 800 IU VitD) or isocaloric control product ( n = 151) for a double-blind period of 13 weeks. At baseline and after 13 weeks, circulating interleukin (IL)-8, IL-1 receptor antagonist (RA), soluble tumor-necrosis-factor receptor (sTNFR)1, IL-6, high-sensitivity C-reactive protein, pre-albumin and 25-hydroxyvitamin(OH)D were measured. Data-analysis included repeated measures analysis of covariance (corrected for dietary VitD intake) and linear regression. Results IL-6 and IL-1Ra serum levels showed overall increases after 13 weeks ( p = 0.006 and p < 0.001, respectively). For IL-6 a significant time × treatment interaction ( p = 0.046) was observed, with no significant change over time in the active group ( p = 0.155) compared to control (significant increase p = 0.012). IL-8 showed an overall significant decrease ( p = 0.03). The change in pre-albumin was a significant predictor for changes in IL-6 after 13 weeks. Conclusions We conclude that 13 weeks of nutritional supplementation with VitD and leucine-enriched whey protein may attenuate the progression of CLIP in older sarcopenic persons with mobility limitations. Electronic supplementary material The online version of this article (10.1007/s40520-019-01208-4) contains supplementary material, which is available to authorized users.

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“…The branched chain amino acids (BCAA) leucine, isoleucine and valine, which are essential amino acids in animals ( 186 ), are important for growth, development and immunity ( 187 , 188 ). Leucine (Leu) acts as a nutrient signal that regulates T-cells by activating mTORC1 ( 189 ).…”

Section: Amino Acid Metabolism and Crustacean Immunitymentioning

confidence: 99%

Modulation of Crustacean Innate Immune Response by Amino Acids and Their Metabolites: Inferences From Other Species

et al. 2020

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Aquaculture production of crustaceans (mainly shrimp and crabs) has expanded globally, but disease outbreaks and pathogenic infections have hampered production in the last two decades. As invertebrates, crustaceans lack an adaptive immune system and mainly defend and protect themselves using their innate immune system. The immune system derives energy and metabolites from nutrients, with amino acids constituting one such source. A growing number of studies have shown that amino acids and their metabolites are involved in the activation, synthesis, proliferation, and differentiation of immune cells, as well as in the activation of immune related signaling pathways, reduction of inflammatory response and regulation of oxidative stress. Key enzymes in amino acid metabolism have also been implicated in the regulation of the immune system. Here, we reviewed the role played by amino acids and their metabolites in immune-modulation in crustaceans. Information is inferred from mammals and fish where none exists for crustaceans. Research themes are identified and the relevant research gaps highlighted for further studies.

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Immunomodulatory role of branched-chain amino acids

Cited by 49 publications

References 209 publications

Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

Thirteen weeks of supplementation of vitamin D and leucine-enriched whey protein nutritional supplement attenuates chronic low-grade inflammation in sarcopenic older adults: the PROVIDE study

Modulation of Crustacean Innate Immune Response by Amino Acids and Their Metabolites: Inferences From Other Species

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