Scientists at the Baylor College of Medicine, Stanford University School of Medicine, and collaborating institutions published a study, “A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites,” in Cell about the discovery of BHB-Phe, a novel compound produced by the body that regulates appetite and body weight through interactions with neurons in the brain.
Until now, β-Hydroxybutyrate (BHB) has been known as a compound produced by the liver to be used as fuel. However, in recent years, scientists have found that BHB increases in the body after fasting or exercise, prompting interest in investigating potential beneficial applications in obesity and diabetes.
In the current study with mice, the team at Stanford University led by co-corresponding author Jonathan Z. Long, PhD, associate professor of pathology, 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, BHB-Phe, can influence body weight and metabolism in animal models.
How BHB-Phe influences feeding behavior and body weight in mice
The Baylor team, headed by co-corresponding author Yong Xu, MD, PhD, professor of pediatrics and nutrition, and associate director of basic sciences at the USDA/ARS Children’s Nutrition Researcher Center at Baylor, took on the task of investigating how BHB-Phe influences feeding behavior and body weight in mice.
“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. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids,” the investigators wrote.
“Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans.
“Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.”
“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,” 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.”
The CNDP2 enzyme that produces BHB-Phe also produces a related compound called Lac-Phe, previously discovered by the authors. Lac-Phe, the researchers reported in Nature, is a compound in the blood that is produced during exercise and can reduce food intake and obesity in mice. 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,” Xu said. “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,” Long said. “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.”
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