Unlocking the secrets of ketosis

The ketogenic “keto” diet and intermittent fasting have surged in popularity, embraced by everyone from weekend warriors to endurance athletes. These trends promise to harness the power of ketosis — a metabolic state where the body burns fat for energy instead of carbohydrates. Advocates tout its benefits, from weight loss to neuroprotection.

A collaborative research team is now tackling the unanswered questions surrounding ketosis. 

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.

“It turns out ketosis is not a monolithic state," said Long. "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."

The research — published November 12, 2024 in Cell — was made possible by research grants from the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute, and the Stanford Wu Tsai Human Performance Alliance agility project, alongside other funding sources (see below for details).

A new chapter in metabolic science

When deprived of glucose — its primary energy source — the body shifts gears, 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.

Long and his team weren’t so sure. They 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.

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

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.

"If pathways are like the highway system, shunts are the off-ramps," Long explained. "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."

Ketones in the brain

The discovery of this ketone shunt suggests that ketones have additional, previously unrecognized roles in the body’s metabolic landscape. The critical question remained: Are they inert byproducts, or do they actively influence the body’s response to ketosis?

To answer these questions, 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.

“When I’m fasting or losing weight, I don’t feel as hungry,” said Long. “That’s a well-established aspect of ketosis, tied to the neurobiology of feeding and energy balance.”

Further, the 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, raising 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. “This third, shunt pathway turns out to be important for the regulation of appetite and ketosis-associated weight loss,” said Long.

Implications for Therapy and Research

By uncovering 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, “our basic understanding [of ketosis] was actually incomplete,” said Long. “Now, we can revisit all these phenomena through a new lens.”

For instance, while it’s well established that the ketogenic diet is uniquely effective in controlling seizures in children with drug-resistant epilepsy, it remains unclear whether other benefits, such as improved cognition or metabolic health, are real — and, if so, how they work. The identification of these metabolites offers a new framework for investigating these effects systematically.

What’s Next? 

In fact, Long and his collaborators are already revisiting epilepsy with support from the Wu Tsai Neurosciences Institute. 

Collaborating with Dr. Juliette Knowles, a clinical expert in epilepsy at Stanford, Long is investigating whether the newly identified shunt pathway and its metabolites play a role in seizure control. If so, this could open the door to novel treatments that replicate the benefits of ketosis without requiring a strict dietary regimen.

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.

“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,” said Long.

Citation

This article refers to: “A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.” Moya-Garzon, Maria Dolores et al. Cell. Published online November 12, 2024. https://doi.org/10.1016/j.cell.2024.10.032

Acknowledgments

This work was supported by the NIH (DK124265 and DK130541 to J.Z.L.; DK125260, DK111916, and P30DK116074 to K.J.S.; GM113854 to V.L.L.; HD112123 to M.W.; K99AR081618 to M.Z.; T32HL161270 to C.P.W.; R00AG058801 to E.L.G.; and T32GM136631 to A.S.-H.T.), the Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute (research grant to J.Z.L.), the Ono Pharma Foundation (research grant to J.Z.L.), the Stanford Wu Tsai Human Performance Alliance (research grant to J.Z.L. and fellowship to X.L. and M.D.M.-G.), the Stanford Bio-X (SIGF graduate student fellowship to V.L.L.), the Jacob Churg Foundation (research grants to J.Z.L. and K.J.S.), the American Heart Association (fellowship #905674 to M.Z.), the Stanford School of Medicine (Dean’s postdoctoral fellowship to L.C.), the Independent Research Fund Denmark (2030-00007A to S.H.R.), the Lundbeck Foundation (R380-2021-1451 to S.H.R.), the American Heart Association (24POST1196199 to W.W.), the CIHR (PJ9-166217 and PJT-169116 to J.P.L.), the Ovarian Cancer Research Alliance (MIG-2023-2-1015 to A.D.-G.), the Fundación Alfonso Martin Escudero (fellowship to M.D.M.-G. and A.D.-G.), and USDA/CRIS (51000-064-01S to Y.X.).

Declaration of interests

A provisional patent application has been filed by Stanford University on BHB-amino acids for the treatment of cardiometabolic disease.