Branched‐chain amino acids differently modulate catabolic and anabolic states in mammals: a pharmacological point of view

Bifari, Francesco; Nisoli, Enzo

doi:10.1111/bph.13624

Cited by 122 publications

(110 citation statements)

References 121 publications

(146 reference statements)

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“…This is in line with previous molecular investigations which show lipids (such as palmitate) depress metabolic regulator activity (such as PGC‐1α or insulin sensitivity) which in part governs BCAT and BCKDH expression and activity (described in greater detail below) . Thus in the presence of energy excess, BCKDH activity appears to be inhibited thereby promoting the accumulation of BCAAs, and possibly independent of excess BCAA consumption . Additionally, several experimental findings described above using various models of obesity and metabolic disease did not report elevated BCAA circulation (excluding the individual BCAAs used as treatments).…”

Section: Relationship Between Circulating Bcaas and Insulin Resistancesupporting

confidence: 88%

“…[107] Thus in the presence of energy excess, BCKDH activity appears to be inhibited thereby promoting the accumulation of BCAAs, and possibly independent of excess BCAA consumption. [94] Additionally, several experimental findings described above using various models of obesity and metabolic disease did not report elevated BCAA circulation (excluding the individual BCAAs used as treatments). For example, male C57BL/6J mice fed a HF diet with or without leucine supplementation (1.5% wt/vol, drinking water) only displayed elevated leucine, and significantly improved glucose response following IP injection versus HF-only fed mice.…”

Section: Rodent Studiesmentioning

confidence: 97%

“…Not coincidentally, because expression of BCAA‐degradation enzymes is highly dependent on energy circumstances, hormones, and various other factors such as exercise, it has been previously observed that obesity and HF feedings suppress the expression of enzymes which catabolize BCAAs . For example, Lackey et al.…”

Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 99%

“…As described briefly in the introduction, elevated circulating BCAAs have been observed to be highly related to metabolic disease, especially insulin resistance [86][87][88][89][90][91][92][93] (a relationship which is not under dispute in this report), however the interplay between circulating BCAAs and metabolic disease is highly complex. [94] In fact, elevated circulating BCAAs may be a product of several factors, although despite being essential in nature, dietary protein intake doesn't appear to correlate with circulating BCAA values. [95] Thus, dysregulated BCAA catabolism (a process discussed more below) is thought to be a chief cause of elevated BCAA concentrations observed in circulation of diabetics.…”

Section: Human Studiesmentioning

confidence: 99%

“…Both catalytic and regulatory enzyme activity is governed by covalent and allosteric enzyme modifications, as well as at the expressional level, [22] all of which may be influenced by nutrient availability, [119] exercise, [120] and hormones. [119] Not coincidentally, because expression of BCAA-degradation enzymes is highly dependent on energy circumstances, hormones, and various other factors such as exercise, [86,94,120] it has been previously observed that obesity and HF feedings suppress the expression of enzymes which catabolize BCAAs. [92,104] For example, Lackey et al demonstrated significantly reduced BCKDH expression in adipose of lean C57BL/J6 mice fed dietary lipid at either 45% or 60% of diet compared with mice fed 10% lipid diet.…”

Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 99%

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BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

Gannon

Schnuck

Vaughan

2018

Molecular Nutrition Food Res

135

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Branched-chain amino acids (BCAAs) appear to influence several synthetic and catabolic cellular signaling cascades leading to altered phenotypes in mammals. BCAAs are most notably known to increase protein synthesis through modulating protein translation, explaining their appeal to resistance and endurance athletes for muscle hypertrophy, expedited recovery, and preservation of lean body mass. In addition to anabolic effects, BCAAs may increase mitochondrial content in skeletal muscle and adipocytes, possibly enhancing oxidative capacity. However, elevated circulating BCAA levels have been correlated with severity of insulin resistance. It is hypothesized that elevated circulating BCAAs observed in insulin resistance may result from dysregulated BCAA degradation. This review summarizes original reports that investigated the ability of BCAAs to alter glucose uptake in consequential cell types and experimental models. The review also discusses the interplay of BCAAs with other metabolic factors, and the role of excess lipid (and possibly energy excess) in the dysregulation of BCAA catabolism. Lastly, this article provides a working hypothesis of the mechanism(s) by which lipids may contribute to altered BCAA catabolism, which often accompanies metabolic disease.

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Section: Relationship Between Circulating Bcaas and Insulin Resistancesupporting

confidence: 88%

Section: Rodent Studiesmentioning

confidence: 97%

Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 99%

Section: Human Studiesmentioning

confidence: 99%

Section: Molecular Hypothesis Of the Metabolic Dysregulation Of Bcaa mentioning

confidence: 99%

See 3 more Smart Citations

BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

Gannon

Schnuck

Vaughan

2018

Molecular Nutrition Food Res

135

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High Protein Intake Is Associated With Histological Disease Activity in Patients With NAFLD

Lang

Martin²,

Farowski

et al. 2020

Hepatol Commun

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Overconsumption of carbohydrates and lipids are well known to cause nonalcoholic fatty liver disease (NAFLD), while the role of nutritional protein intake is less clear. In Western diet, meat and other animal products are the main protein source, with varying concentrations of specific amino acids. Whether the amount or composition of protein intake is associated with a higher risk for disease severity has not yet been examined. In this study, we investigated associations of dietary components with histological disease activity by analyzing detailed 14-day food records in a cohort of 61 patients with biopsy-proven NAFLD. Furthermore, we used 16S ribosomal RNA gene sequencing to detect associations with different abundances of the gut microbiota with dietary patterns. Patients with definite nonalcoholic steatohepatitis (NAFLD activity score of 5-8 on liver biopsy) had a significantly higher daily relative intake of protein compared with patients with a NAFLD activity score of 0-4 (18.0% vs. 15.8% of daily protein-based calories, P = 0.018). After adjustment for several potentially confounding factors, a higher protein intake (≥17.3% of daily protein-based calories) remained associated with definite nonalcoholic steatohepatitis, with an odds ratio of 5.09 (95% confidence interval 1.22-21.25, P = 0.026). This association was driven primarily by serine, glycine, arginine, proline, phenylalanine, and methionine. A higher protein intake correlated with a lower Bacteroides abundance and an altered abundance of several other bacterial taxa. Conclusion: A high protein intake was independently associated with more active and severe histological disease activity in patients with NAFLD. Further studies are needed to investigate the potential harmful role of dietary amino acids on NAFLD, with special attention to meat as their major source. (Hepatology Communications 2020;4:681-695).

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Bckdk‐Mediated Branch Chain Amino Acid Metabolism Reprogramming Contributes to Muscle Atrophy during Cancer Cachexia

Chen,

Zhang,

Chi

et al. 2023

Molecular Nutrition Food Res

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ScopeBranched chain amino acids (BCAAs) are essential amino acids and important nutrient signals for energy and protein supplementation. The study uses muscle‐specific branched‐chain α‐keto acid dehydrogenase kinase (Bckdk) conditional knockout (cKO) mice to reveal the contribution of BCAA metabolic dysfunction to muscle wasting.Method and resultsMuscle‐specific Bckdk‐cKO mice are generated through crossbreeding of Bckdkf/f mice with Myf5Cre mice. Lewis lung cancer (LLC) tumor transplantation is used to establish the cancer cachexia model. The occurrence of cancer cachexia is accelerated in the muscle‐specific Bckdk‐cKO mice after bearing LLC tumor. Wasting skeletal muscle is characterized by increased protein ubiquitination degradation and impaired protein synthesis. The wasting muscle gastrocnemius is mechanized as a distinct BCAA metabolic dysfunction. Based on the atrophy phenotype resulting from BCAA metabolism dysfunction, the optimized BCAA supplementation improves the survival of cancer cachexia in muscle‐specific Bckdk‐cKO mice bearing LLC tumors, and improves the occurrence of cancer cachexia. The mechanism of BCAA supplementation on muscle mass preservation is based on the promotion of protein synthesis and the inhibition of protein ubiquitination degradation.ConclusionsDysfunctional BCAA metabolism contributes to the inhibition of protein synthesis and increases protein degradation in the cancer cachexia model of muscle‐specific Bckdk‐cKO mice bearing LLC tumors. The reprogramming of BCAA catabolism exerts therapeutic effects by stimulating protein synthesis and inhibiting protein degradation in skeletal muscle.

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Branched‐chain amino acids differently modulate catabolic and anabolic states in mammals: a pharmacological point of view

Cited by 122 publications

References 121 publications

BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

High Protein Intake Is Associated With Histological Disease Activity in Patients With NAFLD

Bckdk‐Mediated Branch Chain Amino Acid Metabolism Reprogramming Contributes to Muscle Atrophy during Cancer Cachexia

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