Effect of branched-chain amino acid supplementation, dietary intake and circulating levels in cardiometabolic diseases

O, Víctor de la; Zazpe, Itzíar; Ruiz‐Canela, Miguel

doi:10.1097/mco.0000000000000614

Cited by 24 publications

(19 citation statements)

References 46 publications

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“…Other studies have shown associations of higher plasma BCAA concentrations with pediatric obesity [38] and insulin resistance [38,65] among adolescents. Recent reports show that BCAA is also independently associated with cardiovascular mortality [66] and cardiometabolic risk [67]. Furthermore, we found SCAAs to be positively associated with BMIz, WHtR, and fat mass, which remained significant even after controlling for several other possible confounders.…”

Section: Discussionsupporting

confidence: 67%

Animal Protein Intake Is Associated with General Adiposity in Adolescents: The Teen Food and Development Study

et al. 2019

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Protein plays a crucial role in the growth and development of adolescents. However, being a secondary energy source, protein’s role in obesity has been sidelined. We examined whether intake of protein (total, animal, plant), branched-chain (BCAAs), and sulfur-containing (SCAAs) amino acids are associated with general body and central obesity and body composition in a cross-sectional study among healthy adolescents. Students aged 12–18 years old (n = 601) in schools near two major Adventist universities in California and Michigan provided dietary data via a validated web-based food frequency questionnaire (FFQ) and anthropometric data during school visits. Intakes of total, animal, and plant proteins, and BCAAs and SCAAs were derived from FFQ data. We defined general body obesity with body-mass-index-for-age (BMIz) z-scores and central obesity with waist-to-height ratios (WHtR). After full adjustment for covariates, multiple regression analyses showed significant positive associations between intakes of total protein (β = 0.101, 95% CI: 0.041, 0.161), animal protein (β = 0.118, 95% CI: 0.057, 0.178), BCAAs (β = 0.056, 95% CI: 0.025, 0.087), and SCAAs (β = 0.025, 95% CI: 0.012, 0.038) with general body adiposity. Animal protein (β = 0.017, 95% CI: 0.001, 0.033) and SCAAs (β = 0.004, 95% CI: 0.000, 0.008) were also associated with central obesity. Total and animal protein and BCAA and SCAA were also significantly associated with fat mass. Our findings suggest that high protein intake may pose a possible detriment to adolescent health. Longitudinal and safety evaluation studies are recommended.

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Section: Discussionsupporting

confidence: 67%

Animal Protein Intake Is Associated with General Adiposity in Adolescents: The Teen Food and Development Study

et al. 2019

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“…BCAAs upregulate glucose transporters and activate insulin secretion (2) . High BCAA levels activate the mammalian target of rapamycin complex one (mTORC1) that could be linked to the insulin resistance (1) . Elevated levels of blood insulin could cause alteration in the insulin-like growth factor (IGF), which is involved in the development of CRC (18) .…”

Section: Discussionmentioning

confidence: 99%

“…Their main sources are meat, fish, legumes, dairy products and eggs. An adequate intake of BCAA is required for protein synthesis and several metabolic and signalling functions, including insulin metabolism (1,2) .…”

mentioning

confidence: 99%

“…Several studies suggested positive associations between dietary or plasma BCAA and the risk of various diseases, including insulin resistance, type 2 diabetes, obesity, CVD and pancreatic cancer (1,3,4) , which may share aetiological aspects and mechanisms with colorectal cancer (CRC). There is evidence of an elevated risk of CRC with higher consumption of red meat (5) , the most major source of BCAA.…”

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confidence: 99%

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Dietary intake of branched-chain amino acids and colorectal cancer risk

et al. 2020

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ABSTACT An adequate intake of branched-chain amino acids (BCAAs) is required for protein synthesis and metabolic functions, including insulin metabolism. Emerging studies found positive associations between BCAAs and the risk of various diseases sharing etiological aspects with colorectal cancer (CRC), including type 2 diabetes, obesity, and pancreatic cancer. We investigated the relation between dietary BCAAs and CRC using data from a multicentric Italian case-control study, including 1953 cases of CRC (of these, 442 of sigmoid colon) and 4154 hospital controls with acute, non-neoplastic diseases. A validated food-frequency questionnaire was used to estimate the participants’ usual diet and to assess dietary intakes of various nutrients, including energy, BCAAs and calcium. Odds ratio (ORs) and corresponding confidence intervals (CI) were computed by multiple logistic regression models adjusted for age, sex and other confounding factors, including total energy intake. BCAA intake was inversely related to CRC risk (OR for the highest versus the lowest quintile, 0.73; 95% CI, 0.55-0.97), but the association was attenuated after adjustment for calcium intake (OR, 0.90; 95% CI, 0.65-1.25). A linear inverse association with sigmoid colon cancer risk remained also after adjustment for other dietary factors, including calcium intake (OR, 0.49; 95% CI, 0.27-0.87). This study provides supporting evidence that higher levels of dietary BCAA intake are not associated with an increase of CRC risk, but confirms that they may be related to a reduced risk of sigmoid colon cancer.

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“…Branched-chain amino acids (BCAAs) and their catabolites are bioactive molecules with a broad repertoire of metabolic actions in cellular health and disease (1)(2)(3)(4)(5)(6). Leucine, isoleucine and valine (BCAAs) are reversibly transaminated by branched-chain aminotransferase (BCAT) to yield branchedchain α-keto acids (BCKA), specifically -ketoisocaproate or ketoleucine (-KIC), -ketoisovalerate or ketovaline (-KIV), and -kethomethylvalerate or ketoisoleucine (-KMV).…”

Section: Introductionmentioning

confidence: 99%

Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling

Biswas

Dao

Mercer

et al. 2020

Preprint

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AbbreviationsAcadm, Acyl-Coenzyme A dehydrogenase, medium chain; BCAAs, branched-chain amino acids; BCKAs, branched-chain keto acids; BCATm, mitochondrial branched chain aminotransferase; BCKDH, branchedchain α-keto acid dehydrogenase; BCKDK, branched-chain keto acid dehydrogenase kinase; BT2, 3,6dichlorobenzo [b]thiophene-2-carboxylic acid; Cyclo, Cyclophilin; DIO, diet induced obesity; Glut, glucose transporter; Hadh, Hydroxyacyl-Coenzyme A dehydrogenase; HFD, high fat diet; HFHS, high fat high sucrose diet; Hmgcs1, 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1; IR, insulin resistance; Ivd2, Isovaleryl-CoA dehydrogenase; KIC, α-ketoisocaproic acid; KLF15, Kruppel like factor-15; mTOR, mammalian target of rapamycin; Mut, methylmalonyl-Coenzyme A mutase; PDH, pyruvate dehydrogenase; PPM1K, mitochondrial-targeted protein phosphatase; Rer1, Retention in endoplasmic reticulum sorting receptor 1; Rpl41, Ribosomal protein L41; Rpl7l1, Ribosomal protein L7-like 1; T2D, type 2 diabetes 3 Abstract Branched-chain α-keto acids (BCKAs) are downstream catabolites of branched-chain amino acids (BCAAs). Mitochondrial oxidation of BCKAs is catalyzed by branched-chain ketoacid dehydrogenase (BCKDH), an enzyme sensitive to inhibitory phosphorylation by BCKD kinase (BCKDK). Emerging studies show that defective BCAA catabolism and elevated BCKAs levels correlate with glucose intolerance and cardiac dysfunction. However, if/how BCKDH and BCKDK exert control on the availability and flux of intramyocellular BCKAs and if BCKA reprograms nutrient metabolism by influencing insulin action remains unexplored. We observed altered BCAA catabolizing enzyme expression in the murine heart and skeletal muscle during physiological fasting and diet-induced obesity and after ex vivo exposure of C2C12 cells to increasing concentration of saturated fatty acid, palmitate. BCKAs per se impaired insulin-induced AKT phosphorylation and AKT activity in skeletal myotubes and cardiomyocytes. In skeletal muscle cells, mTORC1 and protein translation signaling was enhanced by BCKA with concomitant suppression of mitochondrial respiration. Lowering intracellular BCKA levels by genetic and pharmacological activation of BCKDHA enhanced insulin signaling and activated pyruvate dehydrogenase, an effector of glucose oxidation and substrate metabolism. Our findings suggest that BCKAs profoundly influence muscle insulin function, providing new insight into the molecular nexus of BCAA metabolism and signaling with cellular insulin action and respiration.

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Effect of branched-chain amino acid supplementation, dietary intake and circulating levels in cardiometabolic diseases

Cited by 24 publications

References 46 publications

Animal Protein Intake Is Associated with General Adiposity in Adolescents: The Teen Food and Development Study

Animal Protein Intake Is Associated with General Adiposity in Adolescents: The Teen Food and Development Study

Dietary intake of branched-chain amino acids and colorectal cancer risk

Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling

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