A Stanford-led team has discovered a new ketosis pathway involving BHB-amino acids, shedding light on its effects like appetite suppression and offering new avenues for research and therapy. The collaborative research, published in Cell, is now tackling the unanswered questions surrounding ketosis.
What is ketosis?
Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body’s acid–base homeostasis is maintained.
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than carbohydrates.
What does the research say?
The ketogenic diet, commonly known as ‘keto’, and intermittent fasting have gained widespread popularity, attracting everyone from casual fitness enthusiasts to endurance athletes. Both approaches aim to leverage ketosis. Proponents highlight a range of benefits, including weight loss and enhanced brain health.
However, rather than adding to the growing, and often confusing, literature on the effects of ketogenic diets, the team — led by Jonathan Long, an associate professor of pathology at Stanford Medicine and institute scholar at Sarafan ChEM-H, and co-led by Yong Xu, professor of pediatrics at Baylor College of Medicine — are focused on the underlying chemistry of ketones themselves.
Their discovery — a previously unknown metabolic pathway and a family of ‘keto’ metabolites — could rewrite our understanding of how ketosis influences metabolism, including in the brain.
As Long said, “It turns out ketosis is not a monolithic state. There’s a lot more complexity and nuance in how the body processes ketone molecules, and this could explain some of its more intriguing effects.”
Metabolism and all about that:
Metabolism is the science of the chemical reactions that occur in living organisms, including the breakdown of nutrients, the building and repair of the body, and the elimination of waste. The word metabolism comes from the Greek word metabolē, which means ‘to change’.
The science of metabolic diets is based on the idea that changing what and when you eat can affect your metabolism, allowing your body to burn fat instead of storing it. However, research suggests that metabolism is generally stable and that the few exceptions are not good weight-loss strategies.
When deprived of glucose — its primary energy source — the body starts breaking down fat to produce ketones as an alternative fuel. Central to this process is beta-hydroxybutyrate (BHB), the most abundant ketone body.
Until now, scientists believed ketosis followed two main biochemical pathways: ketogenesis, which produces BHB in the liver, and ketolysis (or ketone oxidation) which consumes BHB for energy throughout the body. These pathways were thought to tell the whole story.
Now, for their study, Long and his team decided to take another look at what ketones, particularly BHB, were doing in the body. Rather than diving into the already contentious literature on the ketogenic diet’s downstream effects — such as its potential benefits for cognition or metabolic health — they decided to take a step back.
In a series of experiments on mice and humans, the researchers manipulated the availability of BHB to explore how it influences metabolism and energy balance. What they found was a previously unknown metabolic “shunt pathway,” where enzymes attach BHB to amino acids, producing a family of compounds they dubbed BHB-amino acids.
Long explained, “If pathways are like the highway system, shunts are the off-ramps. What we’re saying is, this is not the main pathway that’s directing traffic, but it gets you somewhere very interesting and unusual off the main road.”
How do ketones impact the body?
The discovery of ketone shunt suggests that ketones have additional, previously unrecognized roles in the body’s metabolic landscape. The critical question here is – are they inert byproducts, or do they actively influence the body’s response to ketosis?
Long and his collaborators zeroed in on the brain — a focus driven by a well-documented phenomenon: when people are in ketosis, their hunger often decreases. He said, “When I’m fasting or losing weight, I don’t feel as hungry. That’s a well-established aspect of ketosis, tied to the neurobiology of feeding and energy balance.”
The research team noticed that the metabolites they were studying chemically resembled another molecule recently discovered by Long and colleagues that is known to regulate hunger and appetite: Lac-Phe. Lac-Phe is produced in the body after sprint exercise, and functions to reduce appetite. This chemical resemblance guided their investigation and raised the question, could these ketone metabolites play an active role in appetite suppression and weight regulation under ketosis conditions?
The researchers found that BHB-amino acids suppress feeding behaviors and promote weight loss, revealing a potent link between ketosis and energy regulation. As per Long, “This third, shunt pathway turns out to be important for the regulation of appetite and ketosis-associated weight loss.”
Implications of the research:
By discovering this previously unknown pathway, the researchers have created an opportunity to revisit longstanding questions about the mechanisms behind the ketogenic diet’s purported benefits.
Until now, as per Long, “our basic understanding [of ketosis] was actually incomplete.” He added, “Now, we can revisit all these phenomena through a new lens.”
As the team continues to probe the fundamental biology of ketosis, their work could pave the way for a deeper understanding of its therapeutic potential — not just for epilepsy but for a range of metabolic and neurological conditions. Long concludes, “Now that we have a better understanding of these pathways, we can ask much better questions about how and why these products might work — and what risks or limitations they might carry.”