Branched Chain Amino Acids, Androgen Hormones, and Metabolic Risk Across Early Adolescence: A Prospective Study in Project Viva

Abstract

Objective To examine associations of two obesity-related metabolite patterns with changes in metabolic biomarkers during early adolescence. Methods Using multivariable linear regression, we examined associations of a branched chain amino acid (BCAA) and androgen hormone patterns with changes in glycemia (fasting glucose, insulin, HOMA-IR), adipokines (leptin, adiponectin), inflammation (C-reactive protein, interleukin-6), lipid profile, and blood pressure during ~5 years follow-up among 213 children aged 6–10 years at baseline. We adjusted for baseline age, pubertal status, biomarker level, and BMI percentile; and age at follow-up. We also tested for interactions with sex and baseline BMI percentile. Results Median age at baseline was 7.7 years; 48.8% were boys. In adjusted models, each 1 unit of the BCAA pattern corresponded with a 4.82 (95% CI: 0.92, 8.71) mg/dL decrease in fasting glucose in boys. In girls, the BCAA pattern was associated with an increase in triglycerides (4.17 [0.03, 8.32] mg/dL). The androgen pattern was associated with decreased leptin (−2.35 [−4.34, −0.35] ng/dL) and increased CRP (0.28 [0.03, 0.54] mg/dL) in girls. These relationships did not differ by baseline BMI percentile. Conclusions The BCAA and androgen hormone metabolite patterns are related to changes in metabolic parameters in a sex-specific manner during early adolescence.

Longitudinal relationship of amino acids and indole metabolites with long-term body mass index and cardiometabolic risk markers in young individuals

“…This includes a study reporting that high BMI was associated with a decreased KTR in males, but not www.nature.com/scientificreports www.nature.com/scientificreports/ in females 14 . Moreover, BCCAs were associated with a decreased FPG in males, but increased triglycerides in females 23 as well as with a decreased adiponectin in males, but with increased triglycerides to HDL-C ratio in females 24 . The fact these studies 14,23,24 and ours consistently showed inverse associations in males suggest that our findings are unlikely to be spurious.…”

“…Moreover, BCCAs were associated with a decreased FPG in males, but increased triglycerides in females 23 as well as with a decreased adiponectin in males, but with increased triglycerides to HDL-C ratio in females 24 . The fact these studies 14,23,24 and ours consistently showed inverse associations in males suggest that our findings are unlikely to be spurious. Possible explanations for these observed sex-specific findings include sex-related differences in protein turnover, amino acid handling systems, and the influence of sex hormones 33 .…”

“…The positive associations include branched-chain amino acids (BCAAs) with insulin resistance (IR) 15,21,22 , triglycerides 23 , and triglycerides to high-density lipoprotein-cholesterol (HDL-C) ratio 24 ; valine, leucine, and isoleucine 10 , phenylalanine and tyrosine 21 , and kynurenine and KTR 25 with IR; cysteine with fasting plasma glucose (FPG), leptin, and IR; 12 indole-3 propionic acid with HDL-C 16 ; arginine, histidine, and serine with insulin sensitivity 5 ; KTR with C-reactive protein (CRP), interferon-gamma, interleukin (IL)−6, IL-10, and alpha-1-acid glycoprotein 26 ; and isoleucine and valine with IR 27 . The few reported negative associations include BCCAs with FPG 23 and adiponectin 24 ; tryptophan with CRP, interferon-gamma, IL-6, IL-10, and alpha-1-acid glycoprotein 26 ; and numerous amino acids with CRP and IL-6 28 . The relation of BCCA with BCCAs with FPG 23 and adiponectin 24 , and that of isoleucine and valine with IR 27 are restricted to males, while the relation of BCAA with triglycerides 23 , and triglycerides to HDL-C ratio 24 are restricted to females.…”

“…The few reported negative associations include BCCAs with FPG 23 and adiponectin 24 ; tryptophan with CRP, interferon-gamma, IL-6, IL-10, and alpha-1-acid glycoprotein 26 ; and numerous amino acids with CRP and IL-6 28 . The relation of BCCA with BCCAs with FPG 23 and adiponectin 24 , and that of isoleucine and valine with IR 27 are restricted to males, while the relation of BCAA with triglycerides 23 , and triglycerides to HDL-C ratio 24 are restricted to females. The mechanistic involvement of BCCAs in the development of IR includes persistent activation of mTOR signaling pathway and accumulation of toxic BCAA metabolites that trigger mitochondrial dysfunction 29 , and the involvement of tryptophan and KTR in inflammation is through the immunoregulatory role of indoleamine 2,3-dioxygenase 1 30 .…”

Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes

“…Elevated plasma BCAAs have been observed in obese, insulin resistant human adults [6,7] and adolescents [8][9][10][11], postulated to be due to impaired BCAA catabolism. [12,13] Most prior studies in adolescents have examined obese subjects with insulin resistance, but very few have addressed how metabolic pathways are altered in youth with recent onset type 2 diabetes.…”