Acute decrease in the plasma tryptophan-to-large-neutral-amino-acids ratio attenuates the effects of L-tryptophan on gut hormones and energy intake in healthy males: a randomized, cross-over, exploratory trial

BACKGROUND: L-tryptophan ('Trp') and L-leucine ('Leu'), when administered intraduodenally, increase plasma cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) and stimulate pyloric pressures, which all slow gastric emptying and suppress subsequent energy intake. The circulating Trp-to-large-neutral-amino-acids ('Trp/LNAAs') ratio is also inversely related to energy intake.

OBJECTIVE: This exploratory study characterized the impact of standardized changes in the plasma Trp/LNAAs ratio, achieved by combining a fixed-load intraduodenal infusion of Trp with increasing loads of Leu, on the appetite-inhibitory effects of enteral Trp.

METHODS: Twelve males of normal weight (mean±SD; age: 23±2 years; body mass index: 23±1 kg/m²), received on four separate occasions, 90-min iso-osmotic intraduodenal infusions of i) isotonic 0.9% saline ('control'), ii) Trp (0.15 kcal/min; 'Trp'), iii) Trp + Leu (0.22 kcal/min; 'Trp+Leu-0.22'), or iv) Trp + Leu (0.45 kcal/min; 'Trp+Leu-0.45'), in a randomized, double-blind, cross-over fashion. Immediately post-infusion ad-libitum energy intake was quantified. Plasma CCK, GLP-1 and amino acid concentrations, and antropyloroduodenal pressures were measured throughout.

RESULTS: While there was a transient stimulation of CCK and GLP-1 by Trp+Leu-0.45 (at t=15 min), only Trp led to a sustained increase in plasma CCK (P=0.04) and GLP-1 (P=0.009) from t=60-90 min, and stimulated pyloric pressures (P=0.01), compared with control. Only Trp reduced energy intake (kcal (mean±SEM); control: 1085±49, Trp: 881±75, Trp+Leu-0.22: 963±57, Trp+Leu-0.45: 932±60) compared with control (P=0.008). The Trp/LNAAs ratio was dose-dependently decreased by Trp+Leu-0.22 and Trp+Leu-0.45, compared with Trp (all P=0.001), and energy intake correlated inversely with the Trp/LNAAs ratio (R=-0.38; P=0.02).

CONCLUSIONS: Acute reduction in the Trp/LNAAs ratio appears to be associated with a diminished capacity of Trp to stimulate CCK and GLP-1, and suppress energy intake. While these observations should be interpreted with caution given the exploratory nature of the study, they attest to the complexity of the relationships between pre- and post-absorptive mechanisms underlying Trp's appetite-inhibitory effect.

CLINICAL TRIAL REGISTRY: The trial was registered with the Australian New Zealand Clinical Trial Registry (https://www.anzctr.org.au; trial number: ACTRN12620001275954).