Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans

Abstract

Aims/hypotheses: Obesity is associated with decreased insulin sensitivity (IS) and elevated plasma branched-chain amino acids (BCAAs). The purpose of this study was to investigate the relationship between BCAA metabolism and IS in overweight (OW) individuals during exercise intervention.

Methods: Whole-body leucine turnover, IS by hyperinsulinaemic-euglycaemic clamp, and circulating and skeletal muscle amino acids, branched-chain α-keto acids and acylcarnitines were measured in ten healthy controls (Control) and nine OW, untrained, insulin-resistant individuals (OW-Untrained). OW-Untrained then underwent a 6 month aerobic and resistance exercise programme and repeated testing (OW-Trained).

Results: IS was higher in Control vs OW-Untrained and increased significantly following exercise. IS was lower in OW-Trained vs Control expressed relative to body mass, but was not different from Control when normalised to fat-free mass (FFM). Plasma BCAAs and leucine turnover (relative to FFM) were higher in OW-Untrained vs Control, but did not change on average with exercise. Despite this, within individuals, the decrease in molar sum of circulating BCAAs was the best metabolic predictor of improvement in IS. Circulating glycine levels were higher in Control and OW-Trained vs OW-Untrained, and urinary metabolic profiling suggests that exercise induces more efficient elimination of excess acyl groups derived from BCAA and aromatic amino acid (AA) metabolism via formation of urinary glycine adducts.

Conclusions/interpretation: A mechanism involving more efficient elimination of excess acyl groups derived from BCAA and aromatic AA metabolism via glycine conjugation in the liver, rather than increased BCAA disposal through oxidation and turnover, may mediate interactions between exercise, BCAA metabolism and IS.

Trial registration: Clinicaltrials.gov NCT01786941.

Keywords: Branched-chain amino acids; Exercise; Insulin resistance; Metabolomics; Obesity; Protein.

Conflict of interest statement

Duality of interest MJB, JKT and TPR are or were employees of the CV and Metabolic Research Unit, Pfizer. CBN is a paid consultant for the CV and Metabolic Research Unit of Pfizer. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Figures

Fig. 1

Protocol for measurement of whole-body protein turnover. X indicates muscle biopsy and arrows below the figure show time points for blood, breath and urine samples

Fig. 2

Glucose and BCAA homeostasis. OW-Untrained (black bars/squares); OW-Trained (white bars/squares); Control (striped bars/black triangles). OGTT plasma glucose (a), insulin (b), glucose and insulin AUC (c). Steady state GIR during hyperinsulinaemic–euglycaemic clamp relative to body weight (d) and FFM (e). Clamp glucose (f), insulin (g), BCAA (h) and BCAA α-keto acid (i) concentrations. Basal plasma molar sum of BCAAs (j) and BCAA α-keto acids (k). α=0.05. *p<0.05 vs Control; †p<0.05 vs OW-Untrained; ‡p=0.095 vs OW-Untrained at 0 min; §p=0.054, ¶p=0.088 vs Control. Means± SEM. n=9, OW groups; n=10, Controls. aGlucose AUC as (mmol/l×min)/100, Insulin AUC as pmol/l×min (×10−3). bStatistical symbols apply to OW-Trained vs Control and OW-Untrained across all time points. cStatistical symbol applies to OW-Trained vs OW-Untrained across all time points

Fig. 3

Whole-body (WB) leucine turnover and MPS. OW-Untrained (black bars/squares); OW-Trained (white bars/squares); Control (striped bars/black triangles). Leucine turnover relative to body mass (a) and FFM (b). Mixed muscle protein FSR group averages (c) and individual changes in OW groups (d). Steady state venous leucine (e) and phenylalanine (f) enrichment (E). α=0.05. *p<0.05, **p<0.01 vs Control; †p<0.05 vs OW-Untrained. Means±SEM, except in (d). n=9, OW groups (a, b); n=8, OW groups (c–f); n=10, Control

Fig. 4

AAs and urinary metabolites. OW-Untrained (black); OW-Trained (white); Control (striped). AA concentrations (μmol/l) in plasma (a, d) and muscle (b, c, e). Relative abundance of urinary metabolites (f, g). (a–c) α=0.01; (d–g) α=0.05. *p<0.05, **p<0.01 vs Control; †p<0.05, ††p<0.01 vs OW-Untrained. Means±SEM. n=13, OW-Untrained; n=9, OW-Trained; n=10, Control

Fig. 5

Acylcarnitine concentrations in plasma (a–d) and muscle (e–h). OW-Untrained (black); OW-Trained (white); Control (striped). α=0.01. *p<0.05, **p<0.01 vs Control; †p<0.05 vs OW-Untrained. Means±SEM. n=13, OW-Untrained; n=9, OW-Trained; n=10, Control

Fig. 6

Plasma and muscle metabolite factor relationships with GIR. Scatter plots depicting plasma baseline sum of BCAAs (a), Δ sum of BCAAs (b), baseline sum of the BCAA α-keto acids (c), Δ sum of α-keto acids (d) in plasma, and baseline sum of even-chain unsaturated acylcarnitines C8–C18 (e), and Δ sum of C8–18 acylcarnitines (f) in muscle vs ΔGIR, OW participants. **p<0.01. Correlation matrices in ESM Table 4