Researchers have identified a new metabolic pathway that helps explain how ketosis influences metabolism, including in the brain. In ketosis, the body burns fat instead of carbohydrates for energy. The increasingly popular ketogenic diet and intermittent fasting aim to harness the power of this metabolic state. 

Ketogenic or keto diets consist of a daily intake of 10% carbohydrates, 30% protein and 60% fat to reach ketosis. This metabolic state has been linked to a range of health benefits, such as weight loss, neuroprotection and improvements in obesity, type 2 diabetes and epilepsy.

In ketosis, the body produces ketones from fat as an alternative fuel to glucose. Central to this process is beta-hydroxybutyrate (BHB), the most abundant ketone body. Until now, scientists were aware of two main biochemical pathways for ketosis — ketogenesis produces BHB in the liver, and ketolysis or ketone oxidation consumes BHB to generate energy throughout the body.

In their study published in Cell, the researchers focus on the underlying chemistry of ketones. They describe a previously unknown metabolic “shunt pathway,” wher enzymes attach BHB to amino acids, producing a family of compounds they dubbed BHB-amino acids. 

“It turns out ketosis is not a monolithic state,” says lead researcher Jonathan Long, an associate professor of pathology at Stanford Medicine, US. “There’s much more complexity and nuance in how the body processes ketone molecules, which could explain some of its more intriguing effects.”

metabolic shunt pathway

The researchers discovered the new pathway by examining what ketones, particularly BHB, were doing in the body instead of adding to the literature on the keto diet’s health benefits. 

“Let’s just step away from all the purported effects and focus on the chemistry of these metabolites,” says Long. “wher do they come from? wher do they go?”

The team discovered the metabolic “shunt pathway” by conducting experiments on mice and humans. They manipulated BHB’s availability to explore how it influences metabolism and energy balance. This pathway generates BHB-amino acids, which the researchers dub “anti-obesity ketone metabolites.” 

“If pathways are like the highway system, shunts are the off-ramps,” explains Long. “What we’re saying is, this is not the main pathway directing traffic, but it gets you somewher very interesting and unusual off the main road.”

Weight management implications

To determine whether ketones are byproducts of ketosis or influence the body’s response to this process, the team examined how the process impacts the brain. 

Long explains that people in ketosis are often less hungry. “That’s a well-established aspect of ketosis, tied to the neurobiology of feeding and energy balance.”

The researchers discovered that BHB-amino acids can activate feeding-associated regions in the brain and how much people want to eat. The compounds suppress food intake and promote weight loss, revealing a link between ketosis and energy regulation. 

“This third shunt pathway turns out to be important for regulating appetite and ketosis-associated weight loss,” details Long.

The team identified the most abundant BHB-amino acid as BHB-Phe. This metabolite suppresses feeding behavior in mice by activating hypothalamic and brainstem neurons. It also resembles another molecule, Lac-Phe, which Long’s team recently discovered. Lac-Phe is produced in the body after sprint exercise and helps to reduce appetite. 

Implications for future research

The discovery of the previously unknown pathway creates an opportunity to examine further the mechanisms behind the many health benefits linked to keto diets. Long details: “We can revisit all these phenomena through a new lens.”

The team is already revisiting the role of ketosis in epilepsy. Previous research details that a keto diet is effective in controlling seizures in children with drug-resistant epilepsy. 

The research team is collaborating with Dr. Juliette Knowles, a clinical expert in epilepsy at Stanford University, to determine if the shunt pathway and its metabolites also play a role in seizure control. This could “open the door” to novel treatments that replicate ketosis benefits without requiring patients to follow a strict dietary regimen. 

As the researchers continue to examine the biology of ketosis, they could pave the way for a deeper understanding of the process’ therapeutic potential in a range of metabolic and neurological processes. 

For example, scientists suggest that a keto diet or supplements may regulate or restore menstrual cycles by increasing ketone levels. In addition to short- and long-term weight management support, research also links keto diets to dramatic improvements in metabolic function and psychiatric symptoms in patients with severe mental illnesses. 

“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,” concludes Long.