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Until now, β-hydroxybutyrate (BHB) has been known as a compound produced by the liver to be used as fuel. In a new study, researchers discovered that BHB also participates in another metabolic pathway; in this case, an enzyme called CNDP2 joins BHB to amino acids; furthermore, the most abundant BHB-amino acid, N-β-hydroxybutyryl phenylalanine (BHB-Phe), can influence body weight and metabolism in animal models.
β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Moya-Garzon et al. identified a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. Image credit: Moya-Garzon et al., doi: 10.1016/j.cell.2024.10.032.
Mammals have evolved complex nutrient-responsive pathways that link the availability of external energy sources to internal metabolic homeostasis.
These pathways involve changes to cellular energy metabolites, which function both as metabolic fuels and as downstream effectors.
A key example is BHB, a ketone body whose levels rise during periods of low carbohydrate availability, such as during starvation, intermittent fasting, or with consumption of a ketogenic diet.
In the new research, Baylor College of Medicine Professor Yong Xu and colleagues aimed to investigate how BHB-Phe — the most abundant BHB-amino acid — influences feeding behavior and body weight in mice.
“We know that groups of neurons in the brain regulate feeding behavior, so we mapped the entire brain to determine which areas were activated by BHB-Phe,” Professor Xu said.
“We found that BHB-Phe activates neural populations in the hypothalamus and brainstem, and this suppresses feeding and reduces body weight.”
“In contrast, mice genetically modified to not produce CNDP2 and therefore lack BHB-Phe, ate more and gained weight.”
Interestingly, the CNDP2 enzyme that produces BHB-Phe also produces a related compound called Lac-Phe, previously discovered by the team.
“Lac-Phe is a compound in the blood that is produced during exercise and can reduce food intake and obesity in mice,” Professor Xu said.
“But do Lac-Phe and BHB-Phe mediate their common effects by activating the same neurons in the brain?”
“Our analyses showed that only a small proportion of neurons were activated by both compounds; most of the neurons activated by Lac-Phe and BHB-Phe were different.”
“This indicates the possibility that, although both compounds affect feeding behaviors in similar ways, they mediate this effect by different mechanisms.”
The findings suggest that the new pathway involving BHB-Phe, which is also present in people, could be disrupted in obesity and maybe other conditions, supporting the need for further studies to better understand the mechanism.
“This work opens up many new possibilities,” said Dr. Jonathan Long, a researcher at Stanford University.
“For example, it might be possible for people in the future to consume BHB-Phe to drive weight loss without restricting carbohydrates in their diet.”
The findings appear this week in the journal Cell.
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Maria Dolores Moya-Garzon et al. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. Cell, published online November 12, 2024; doi: 10.1016/j.cell.2024.10.032
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