Branched-chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control

Solon-Biet, Samantha M.; Cogger, Victoria C.; Pulpitel, Tamara; Wahl, Devin; Clark, Ximonie; Bagley, Elena E.; Gregoriou, Gabrielle C.; Senior, Alistair M.; Wang, Qiao‐Ping; Brandon, Amanda E.; Perks, Ruth; O’Sullivan, John; Koay, Yen Chin; Bell-Anderson, Kim; Kebede, Melkam A.; Yau, Belinda; Atkinson, Clare; Svineng, Gunbjørg; Dodgson, Timothy; Wali, Jibran A; Piper, Matthew D. W.; Juricic, Paula; Partridge, Linda; Rose, Adam J.; Raubenheimer, David; Cooney, Gregory J.; Couteur, David G. Le; Simpson, Stephen J.

doi:10.1038/s42255-019-0059-2

Cited by 217 publications

(211 citation statements)

References 63 publications

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“…2-7), independent of total dietary AA supply. Importantly, this validates a prior study predicting that Thr is the most limiting AA from AA exome matching under a casein based diet 20 as well as a recent study demonstrating that the hyperphagia due to dietary casein/AA restriction relates to Thr and/or Trp supply 59 . However, here we demonstrate that both Thr and Trp are equally limiting in the casein-based diet through empirical investigation, both by dietary AA restriction and by using a genetic model of AA-transport deficiency ( Fig.…”

Section: Discussion (1814 Words)supporting

confidence: 87%

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

Yap

Rusu

Chan

et al. 2019

Preprint

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words)Dietary protein dilution (DPD) promotes metabolic remodelling and health but the precise nutritional components driving this response remain elusive. Here we demonstrate that dietary amino acids (AA) are sufficient and necessary to drive the response to DPD. In particular, the restriction of dietary essential AA (EAA) supply, but not non-EAA, drives the systemic metabolic response to total AA deprivation. Furthermore, systemic deprivation of Thr and Trp, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Thr is also potentially limiting in low-protein diet fed humans, and dietary Thr restriction (DTR) retarded the development of obesity-associated metabolic dysfunction in mice. Liver-derived fibroblast growth factor 21 was required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of Thr biosynthetic capacity reversed the systemic response to DTR. Taken together, our studies demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD. 4

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Section: Discussion (1814 Words)supporting

confidence: 87%

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

Yap

Rusu

Chan

et al. 2019

Preprint

Self Cite

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“…We also show that this mutualistic relationship buffers the effect of dietary restrictions in both, the microbiome and the host. Diet is an essential, dynamic, and highly diverse environmental variable deeply affecting several aspects of behaviour, including food choice (Leitão-Gonçalves et al, 2017;Simpson et al, 2015;Solon-Biet et al, 2019;Tarlungeanu et al, 2016), as well as the microbiome, which has been shown to play a critical role in human behaviour, including through the metabolism of nutrients and drugs (Dodd et al, 2017;Kessel et al, 2019;Rekdal et al, 2019;Sharon et al, 2019;Smith et al, 2013). Our study highlights the importance of metabolic interactions among different species of gut bacteria in shaping the outcome of diet on the microbiome and its impact on host physiology and behaviour.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, universally, over-ingestion of dietary AAs shortens lifespan and negatively impacts healthspan (Grandison et al, 2009;Levine et al, 2014;Solon-Biet et al, 2014). Given the importance of a balanced dietary intake of AAs, organisms are able to direct their feeding choices to homeostatically compensate both for the lack and over-ingestion of AAs (Gosby et al, 2011;Leitão-Gonçalves et al, 2017;Ribeiro and Dickson, 2010;Simpson et al, 2015;Solon-Biet et al, 2019). In Drosophila melanogaster females, both AA deprivation and mating induce changes in specific neuronal circuits which modulate food choice, leading to a drastic increase in protein appetite, (Ribeiro and Dickson, 2010;Steck et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Metabolic cross-feeding allows a gut microbial community to overcome detrimental diets and alter host behaviour

Henriques

Serra

Francisco

et al. 2019

Preprint

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The impact of commensal bacteria on the host arises from complex microbial-diet-host interactions. Mapping metabolic interactions in gut microbial communities is therefore key to understand how the microbiome influences the host. Here we use an interdisciplinary approach including isotope-resolved metabolomics to show that in Drosophila melanogaster, Acetobacter pomorum (Ap) and Lactobacillus plantarum (Lp) establish a syntrophic relationship to overcome detrimental host diets and identify Ap as the bacterium altering the host's feeding decisions. Specifically, we show that Lp generates lactate which is used by Ap to produce and provide amino acids that are essential to Lp allowing it to grow in imbalanced diets. Lactate is also necessary and sufficient for Ap to alter the fly's protein appetite. Our data show that gut bacterial communities use metabolic interactions to become resilient to detrimental host diets and to ensure the constant flow of metabolites used by effector bacteria to alter host behaviour.Drosophila, feeding behaviour, microbiome, commensal bacteria, nutrition, bacterial communities, essential amino acids, syntrophy, metabolic crossfeeding, Acetobacteracaea, Lactobacilli Correspondence: carlos.ribeiro@neuro.fchampalimaud.org

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“…Glucose and lactate measurements within the plasma and CSF were quantified using a YSI 2900 analyzer as previously described [9]. A detailed description of blood and CSF sample preparation and coefficients of variation for these assays has been published [16,26]. Insulin was measured by ELISA (Mercodia, Uppsala, Sweden) in plasma and CSF samples.…”

Section: Metabolomics Lipids Glucose and Lactate Measuresmentioning

confidence: 99%

“…Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids necessary for protein synthesis, but when found in excess, impact energy homeostasis [13][14][15]. Recent work demonstrated that elevated dietary BCAA intake is associated with obesity and insulin resistance in both humans and rodents [16,17], and plasma BCAA levels are highly predictive of T2D development in normoglycemic individuals [18]. Elevated levels of circulating BCAAs are associated with suppressed mitochondrial β-oxidation, reduced glucose tolerance, increased insulin resistance, and increased de novo lipogenesis, making BCAAs a potential biomarker of metabolic disease [17,19].…”

Section: Introductionmentioning

confidence: 99%

Type-2-diabetes Alters CSF but not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

Kavanagh

Day

Pait

et al. 2019

Preprint

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Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a 2-4 fold increased risk for developing Alzheimer's disease (AD), however the exact mechanisms linking the two disease is unknown. In both conditions, the majority of pathophysiological changes (including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau) occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and AD-related pathology, including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, prediabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to pre-diabetic and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ40 and CSF Aβ42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with our previous studies in mice, CSF Aβ40 and CSF Aβ42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ40 and CSF Aβ42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.

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Branched-chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control

Cited by 217 publications

References 63 publications

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

Metabolic cross-feeding allows a gut microbial community to overcome detrimental diets and alter host behaviour

Type-2-diabetes Alters CSF but not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

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