Mammals have evolved complex nutrient response pathways that link external energy sources with internal metabolic homeostasis. Among these, β-hydroxybutyrate (BHB) is a crucial metabolite whose levels increase when there is insufficient carbohydrate supply, such as during starvation, intermittent fasting, ketogenic diets, or after exercise. This has sparked interest in studying the potential applications of BHB in obesity.
Recently, a team led by Professor Yong Xu from Baylor College of Medicine, in collaboration with Professor Jonathan Z. Long's team from Stanford University, published a research paper titled "A β-hydroxybutyrate shunt pathway generates anti-obesogenic ketone metabolites" in the journal Cell.
This study is the first to reveal that BHB produces BHB-amino acids through a previously unknown secondary metabolic pathway, with the highest concentration being BHB-phenylalanine (BHB-Phe). This compound suppresses appetite and alleviates obesity by activating specific neurons in the hypothalamus and brainstem.
In previous reports, CNDP2 (Carnosine Dipeptidase 2) has been shown to catalyze the condensation reaction of lactic acid with amino acids. Given the structural similarity between BHB and lactic acid, it is hypothesized that BHB might also participate in a similar metabolic pathway involving conjugation with amino acids, leading to the formation of a novel metabolite: N-β-hydroxybutyrylamino acids (BHB-amino acids). The results of this study indicate that CNDP2 can catalyze the synthesis of BHB-amino acids, with BHB-phenylalanine (BHB-Phe) being the most abundant.
CNDP2-dependent BHB-amino acid synthesis reaction
Researchers injected BHB-Phe into diet-induced obese (DIO) mice. The results indicated that BHB-Phe significantly reduced food intake in the mice. Additionally, with long-term injections, the DIO mice consistently exhibited reduced food intake and decreased body weight.
Another study using CNDP2 knockout mouse models showed that the absence of BHB-Phe led to increased body weight and food intake in the mice. This is in contrast to the weight loss observed in normal mice, indicating that the production of BHB-Phe is crucial for regulating body weight and food intake.
BHB-Phe suppresses food intake and body weight
The research team also discovered that BHB-Phe activates neurons in the hypothalamus and brainstem, suppressing feeding and reducing body weight. Additionally, as previously reported, the neurons activated by BHB-Phe partially overlap but are not completely identical to those activated by Lac-Phe.
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Souce: NovoPro 2024-11-28