A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and biochemical study without human clinical trial data.
PubMed 39536746 · doi:10.1016/j.cell.2024.10.032
What was done
Researchers investigated secondary metabolic pathways for beta-hydroxybutyrate (BHB). They evaluated the enzymatic conjugation of BHB and free amino acids by CNDP2 using in vitro assays, CNDP2 knockout (KO) mouse models subjected to exogenous ketone ester supplementation or a ketogenic diet, and assessed conservation of the pathway in humans.
What was found
The abstract reports no quantitative values. It reports that CNDP2 mediates the enzymatic conjugation of BHB to amino acids, forming BHB-amino acids. In mice, genetic ablation of CNDP2 eliminated tissue BHB-ylation activity and lowered BHB-amino acid levels. BHB-Phe activated hypothalamic and brainstem neurons and suppressed feeding, whereas CNDP2-KO mice exhibited increased food intake and weight gain when fed a ketogenic diet or given ketone esters. CNDP2-dependent BHB-ylation was also reported to be conserved in humans.
Why it matters
This study identifies a non-energetic, signaling role for ketone bodies via BHB-amino acid conjugates like BHB-Phe, providing a molecular mechanism linking ketosis to appetite regulation and energy balance.
Limits
The abstract provides no sample sizes, effect sizes, statistical measures, or specific experimental details regarding the human samples. Findings on feeding suppression and weight regulation are primarily demonstrated in rodent knockout models, requiring clinical validation in humans.
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