Researchers at Baylor College of Medicine, Stanford University School of Medicine and collaborating institutions report in the journal Cell 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, 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, the team at Stanford University led by co-corresponding author Dr. Jonathan Z. Long, 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.

The Baylor team, headed by co-corresponding author Dr. Yong Xu, professor of pediatrics – nutrition and associate director of basic sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor, took on the task of investigating how BHB-Phe 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. 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.”

Dr. Yong Xu, professor of pediatrics – nutrition and associate director of basic sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor

Interestingly, 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.”