Endocrine, Obesity

A b-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

β-hydroxybutyrate (BHB) is a ketone body produced during ketosis, known for its roles as an energy source and a signaling molecule.

This study investigated a previously unknown BHB metabolic pathway mediated by the enzyme CNDP2, which binds BHB to amino acids to form bioactive metabolites. The research combined in-vitro experiments, in-vivo studies in mice, and metabolomic analysis of human plasma samples, demonstrating the pathway’s relevance.

Key Findings:

New metabolic pathway:

• CNDP2 catalyzes the conjugation of BHB to specific amino acids, producing metabolites such as BHB-phenylalanine (BHB-Phe).
• BHB-Phe is the most abundant BHB-amino acid, with potent appetite-suppressing effects.

Anti-obesity effects in mice:

• Administration of BHB-Phe reduced food intake and body weight in diet-induced obese mice.
• CNDP2 knockout mice exhibited increased food intake and body weight when consuming a ketogenic diet or ketone esters, highlighting the pathway’s role in energy regulation.

Neurological impact:

• BHB-Phe activated specific neurons in the hypothalamus and brainstem, regions implicated in feeding behaviors, independent of known pathways such as melanocortin or GLP-1 signaling.

Human relevance:

• BHB-amino acids, including BHB-Phe, were detected in human plasma and increased after ketone ester supplementation, demonstrating conservation of this pathway in humans.

In summary, this study reveals a novel BHB metabolic pathway mediated by CNDP2, that generates BHB-amino acid conjugates, such as BHB-Phe. These metabolites suppress food intake and regulate body weight, offering new therapeutic possibilities for obesity. Further research is needed to explore their clinical potential and broader metabolic roles in humans.