The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

Yu, Deyang; Richardson, Nicole; Green, Cara L; Spicer, A.; Murphy, Michaela E; Flores, Victoria; Jang, Cholsoon; Kasza, Ildikó; Nikodémová, Mária; Wakai, Matthew H.; Tomasiewicz, Jay L.; Yang, Shany E.; Miller, Blake R.; Pak, Heidi H.; Brinkman, Jacqueline A.; Rojas, Juan; Quinn, William J.; Cheng, Eunhae P.; Konon, Elizabeth N.; Haider, Lexington R.; Finke, Megan; Sonsalla, Michelle; Alexander, Caroline M.; Rabinowitz, Joshua D.; Baur, Joseph A.; Malecki, Kristen; Lamming, Dudley W.

doi:10.1016/j.cmet.2021.03.025

Cited by 188 publications

(177 citation statements)

References 97 publications

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“…Previous results have demonstrated that excess BCAAs directly contributed to de novo lipogenesis or via increased ACLY phosphorylation mediated by the branched-chain ketoacid dehydrogenase kinase (BCKDK) [ 48 , 49 ]. The latest research demonstrated that a low isoleucine diet reprogramed liver and adipose metabolism by increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis [ 50 ]. Their reports also indicated that restriction of dietary isoleucine or valine promoted metabolic health in mice and that restriction of dietary isoleucine was required for the metabolic benefits of a low-protein diet [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…The latest research demonstrated that a low isoleucine diet reprogramed liver and adipose metabolism by increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis [ 50 ]. Their reports also indicated that restriction of dietary isoleucine or valine promoted metabolic health in mice and that restriction of dietary isoleucine was required for the metabolic benefits of a low-protein diet [ 50 ]. Above these results may indicate the unique roles for each of the dietary BCAAs in the development of NAFLD and liver metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Jian

Miao

Liu

et al. 2021

Oxidative Medicine and Cellular Longevity

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Valine is an important essential amino acid of laying hens. Dietary supplemented with BCAAs ameliorated gut microbiota, whereas elevated blood levels of BCAAs are positively associated with obesity, insulin resistance, and diabetes in both humans and rodents. General controlled nonrepressed (GCN2) kinase plays a crucial role in regulating intestinal inflammation and hepatic fatty acid homeostasis during amino acids deficiency, while GCN2 deficient results in enhanced intestinal inflammation and developed hepatic steatosis. However, how long-term dietary valine impacts gut health and the development of nonalcoholic fatty liver disease (NAFLD) remains unknown. Hence, in the present study, we elucidated the effects of dietary valine on intestinal barrier function, microbial homeostasis, and the development of NAFLD. A total of 960 healthy 33-weeks-old laying hens were randomly divided into five experimental groups and fed with valine at the following different levels in a feeding trial that lasted 8 weeks: 0.59, 0.64, 0.69, 0.74, and 0.79%, respectively. After 8 weeks of treatment, related tissues and cecal contents were obtained for further analysis. The results showed that diet supplemented with valine ameliorated gut health by improving intestinal villus morphology, enhancing intestinal barrier, decreasing cecum pathogenic bacteria abundances such as Fusobacteriota and Deferribacterota, and inhibiting inflammatory response mediated by GCN2. However, long-term intake of high levels of dietary valine (0.74 and 0.79%) accelerated the development of NAFLD of laying hens by promoting lipogenesis and inhibiting fatty acid oxidation mediated by GCN2-eIF2α-ATF4. Furthermore, NAFLD induced by high levels of dietary valine (0.74 and 0.79%) resulted in strengthening oxidative stress, ER stress, and inflammatory response. Our results revealed that high levels of valine are a key regulator of gut health and the adverse metabolic response to NAFLD and suggested reducing dietary valine as a new approach to preventing NAFLD of laying hens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Jian

Miao

Liu

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…For example, a recent study shows that many of the metabolic abnormalities attributed to BCAA are mediated by isoleucine and to a lesser extent valine, with leucine having little to no effect ( Yu et al, 2021 ). Although another recent study in C2C12 did not find an effect of valine on insulin resistance ( Rivera et al, 2020a ), the data from Yu et al (2021) are consistent with a previous report of greater effect of valine (compared to leucine) in inducing insulin resistance of glucose transport in L6 myotubes ( Tavajohi-Fini, 2012 ) and of the effect of the valine metabolite 3-hydroxyusobutyrte (3-HIB) in inducing insulin resistance in skeletal muscle ( Jang et al, 2016 ). Because normally, humans do not consume these AAs singly in isolation, it will be interesting to see the relevance of this in management of insulin resistance.…”

Section: Concluding Comments and Outstanding Questionsmentioning

confidence: 99%

Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism

et al. 2021

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Branched-chain amino acids (BCAAs) are critical for skeletal muscle and whole-body anabolism and energy homeostasis. They also serve as signaling molecules, for example, being able to activate mammalian/mechanistic target of rapamycin complex 1 (mTORC1). This has implication for macronutrient metabolism. However, elevated circulating levels of BCAAs and of their ketoacids as well as impaired catabolism of these amino acids (AAs) are implicated in the development of insulin resistance and its sequelae, including type 2 diabetes, cardiovascular disease, and of some cancers, although other studies indicate supplements of these AAs may help in the management of some chronic diseases. Here, we first reviewed the catabolism of these AAs especially in skeletal muscle as this tissue contributes the most to whole body disposal of the BCAA. We then reviewed emerging mechanisms of control of enzymes involved in regulating BCAA catabolism. Such mechanisms include regulation of their abundance by microRNA and by post translational modifications such as phosphorylation, acetylation, and ubiquitination. We also reviewed implications of impaired metabolism of BCAA for muscle and whole-body metabolism. We comment on outstanding questions in the regulation of catabolism of these AAs, including regulation of the abundance and post-transcriptional/post-translational modification of enzymes that regulate BCAA catabolism, as well the impact of circadian rhythm, age and mTORC1 on these enzymes. Answers to such questions may facilitate emergence of treatment/management options that can help patients suffering from chronic diseases linked to impaired metabolism of the BCAAs.

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“…Although protein-induced insulinemia may acutely improve glucose handling, reports of impaired insulin sensitivity in the longer-term may be due to divergent BCAA profiles in protein sources. Recently, mouse models have identified that the BCAAs valine and isoleucine contribute to abnormal glucose handling [ 172 ]. However, all EAAs, especially leucine, are thought to be important as both signal and substrate for muscle anabolism.…”

Section: Potential Supplements For Type 2 Diabetesmentioning

confidence: 99%

Efficacy of Dietary and Supplementation Interventions for Individuals with Type 2 Diabetes

et al. 2021

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The prevalence of Type 2 diabetes (T2D) is increasing, which creates a large economic burden. Diet is a critical factor in the treatment and management of T2D; however, there are a large number of dietary approaches and a general lack of consensus regarding the efficacy of each. Therefore, the purpose of this narrative review is twofold: (1) to critically evaluate the effects of various dietary strategies on diabetes management and treatment, such as Mediterranean diet, plant-based diet, low-calorie and very low-calorie diets, intermittent fasting, low-carbohydrate and very low-carbohydrate diets, and low glycemic diets and (2) to examine several purported supplements, such as protein, branched-chain amino acids, creatine, and vitamin D to improve glucose control and body composition. This review can serve as a resource for those wanting to evaluate the evidence supporting the various dietary strategies and supplements that may help manage T2D.

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The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

Cited by 188 publications

References 97 publications

Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism

Efficacy of Dietary and Supplementation Interventions for Individuals with Type 2 Diabetes

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