Abstract Introduction β-hydroxybutyrate (BHB), produced during ketosis, can conjugate with amino acids forming BHB-amino acids. D-BHB-phenylalanine (D-BHB-Phe) is the most abundant BHB-amino acid and has been shown to reduce appetite and induce weight loss in mice, but its function and regulation in humans remain unclear. The objective of this study was to determine whether D-BHB-Phe concentrations vary across different degrees and forms of ketosis in humans. Methods Plasma D-BHB-Phe was measured in samples from four clinical cross-over trials (i) after 21 days on a ketogenic diet ( n = 10), (ii) after oral consumption of 30 g ketone salt (KS) and 30 g ketone ester (KE) ( n = 14), (iii) after oral KE at doses of 10, 20 and 40 g ( n = 10) and (iv) after oral versus intravenous KS administration ( n = 8). Results After 21 days of ketogenic dieting, plasma D-BHB-Phe became detectable (median 2.1 nmol/L; range 0.9–19.9), compared with near-undetectable concentrations during the standard diet (median 0; range 0-0.9; p = 0.005). Oral KS and KE increased D-BHB-Phe compared with placebo ( intervention x time , p < 0.001). D-BHB-Phe rose dose-dependently after 10 g, 20 g, and 40 g of KE ( intervention x time , p < 0.001). Oral KS induced higher peak concentrations of D-BHB-Phe (15.6 ± 6.4 nmol/L) compared with iso-ketotic intravenous KS infusion, which elicited only a modest peak (1.5 ± 0.3 nmol/L; intervention x time , p < 0.001). A positive association between the D-BHB and D-BHB-Phe concentration was observed in pooled analyses but was not consistent across cohorts. Conclusion D-BHB-Phe is inducible by ketosis in humans. Our findings suggest involvement of the splanchnic bed in its production and support further exploration of D-BHB-Phe’s role in appetite regulation and metabolic health. Clinical trial registrations NCT05012748, NCT03935841, NCT05263401, NCT05581043.
Pedersen et al. (Wed,) studied this question.