Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness

Abstract

Objective To identify novel biomarkers through metabolomic profiles that distinguish metabolically well (MW) from metabolically unwell (MUW) individuals, independent of body mass index (BMI). Materials/Methods This study was conducted as part of the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) project. Individuals from 3 cohorts were classified as lean (BMI<25 kg/m2), overweight (BMI≥25 kg/m2, BMI<30 kg/m2) or obese (BMI≥30 kg/m2). Cardiometabolic abnormalities were defined as: (1) impaired fasting glucose (≥100mg/dL and ≤126mg/dL); (2) hypertension; (3) triglycerides ≥150 mg/dL; (4) HDL-C <40 mg/dL in men, <50 mg/dL in women); and (5) insulin resistance (calculated Homeostatic Model Assessment (HOMA-IR) index of >5.13). MW individuals were defined as having <2 cardiometabolic abnormalities and MUW individuals had ≥two cardiometabolic abnormalities. Targeted profiling of 55 metabolites used mass-spectroscopy-based methods. Principal components analysis (PCA) was used to reduce the large number of correlated metabolites into clusters of fewer uncorrelated factors. Results Of 1,872 individuals, 410 were lean, 610 were overweight, and 852 were obese. Of lean individuals, 67% were categorized as MUW, whereas 80% of overweight and 87% of obese individuals were MUW. PCA-derived factors with levels that differed the most between MW and MUW groups were factors 4 (branched chain amino acids [BCAA]) [p<.0001], 8 (various metabolites) [p<.0001], and 9 (C4/Ci4, C3, C5 acylcarnitines) [p<.0001] and 10 (amino acids) [p<.0002]. Further, Factor 4, distinguishes MW from MUW individuals independent of BMI. Conclusion BCAA and related metabolites are promising biomarkers that may aid in understanding cardiometabolic health independent of BMI category.

Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk

“…PCA showed that altered plasma levels of AA and some of their metabolites, such as kynurenine (Kyn) and C5 acylcarnitine, are associated with many adiposity markers, as reported by other groups (3,24,33,42,44). One other study had examined associations between levels of glutamine, leucine, isoleucine, phenylalanine, and tyrosine and visceral obesity (25).…”

“…Significantly higher plasma BCAA, aromatic amino acids (AAA), and C3 and C5 acylcarnitine levels are also found among metabolically unwell versus metabolically well individuals, independent of BMI (3). Results regarding alterations in other AA remain inconsistent (3,18,33).…”

Disturbed intestinal nitrogen homeostasis in a mouse model of high-fat diet-induced obesity and glucose intolerance

“…Tai et al have shown that increased levels of some AAs such as alanine, proline, and valine were correlated with insulin resistance in Asian men (52). BCAAs could be considered as novel biomarkers for discrimination of metabolic wellness independent of body mass index (6). It has been asserted that higher concentrations of BCAAs in obesity cause or exacerbate insulin resistance through mechanisms involving activation of the mammalian target of rapamycin (mTOR) (40).…”

Oxidative stress and lipotoxicity

“…The observation that the BCAA catabolic pathway is enriched for carbonylation is intriguing because serum levels of BCAAs are positively associated with obesity and insulin resistance (63)(64)(65)(66)(67)(68). The BCAAs (leucine, isoleucine, and valine) are important sources of succinyl-CoA and acetylCoA to replenish the TCA cycle in adipocytes in order to fuel lipogenesis.…”