The ketogenic diet, also known as the “keto” diet, along with intermittent fasting, has rapidly gained traction among diverse groups, from casual fitness enthusiasts to serious endurance athletes. These dietary strategies aim to unlock the benefits of ketosis, a physiological state where the body shifts its energy source from carbohydrates to fat, effectively burning fat for fuel. Proponents of this approach highlight various advantages, including weight loss and potential neuroprotective effects.
A dedicated research consortium is currently delving into the complex questions that remain unanswered about ketosis. Instead of merely piling on to the extensive and often confusing body of research regarding ketogenic diets, the team—led by Jonathan Long, an associate professor of pathology at Stanford Medicine and an institute scholar at the Sarafan ChEM-H, alongside his colleague Yong Xu, a professor of pediatrics at Baylor College of Medicine—is specifically investigating the intricate chemistry surrounding ketones themselves.
“It turns out ketosis is not a monolithic state,” stated Long, emphasizing the complexity of how the body metabolizes ketone molecules. “There’s a lot more depth and subtlety in how these molecules operate, which could explain many of their fascinating effects.”
The groundbreaking research findings, published on November 12, 2024, in Cell, were facilitated through various research grants, including those from the Knight Initiative for Brain Resilience and the Stanford Wu Tsai Human Performance Alliance agility project, as well as other financial sources.
A New Chapter in Metabolic Science
When deprived of glucose—its main energy supply—the body adapts by mobilizing fat reserves, which are metabolized into ketones to serve as an alternative energy source. Central to this metabolic adaptation is beta-hydroxybutyrate (BHB), recognized as the predominant ketone body.
Historically, scientists have maintained that ketosis is governed by two primary biochemical processes: ketogenesis, which synthesizes BHB in the liver, and ketolysis (or ketone oxidation), which utilizes BHB for energy throughout various tissues. These two pathways were believed to provide a comprehensive understanding of ketosis.
However, Long and his research team harbored doubts about this conventional framework. They opted to reassess the roles of ketones, particularly BHB, within the body. Instead of diving into the highly debated literature concerning the downstream effects of ketogenic diets—such as potential cognitive or metabolic benefits—they chose to recalibrate their focus.
“Let’s just step away from all the purported effects and focus on the chemistry of these metabolites,” Long remarked. “Where do they originate, and where do they distribute?”
In a series of novel experiments conducted on both mice and humans, the research team manipulated BHB availability to investigate its impact on metabolism and energy balance. Notably, they uncovered a previously unidentified metabolic “shunt pathway,” through which enzymes conjugate BHB with amino acids, resulting in a novel family of compounds that they named BHB-amino acids.
“If pathways are akin to a highway system, shunts represent the off-ramps,” Long elaborated. “What we’re indicating is that this pathway may not be the primary route directing metabolic traffic, yet it leads to remarkably intriguing and unexpected destinations off the main thoroughfare.”
Ketones in the Brain
To further probe these metabolic questions, Long and his collaborators zeroed in on the brain, motivated by an observation widely recognized in ketosis research: individuals in a state of ketosis frequently report reduced hunger levels.
“When I’m fasting or losing weight, I notice a diminished sense of hunger,” Long noted. “That’s a well-documented aspect of ketosis, closely linked to the neurobiology encompassing feeding behaviors and energy balance.”
Additionally, the research team observed that the ketone metabolites they were studying bore a striking chemical resemblance to another molecule, Lac-Phe, which has been linked to the regulation of hunger and appetite. Lac-Phe is produced after sprint-like exercise and has been shown to diminish appetite, raising the question of whether these ketone metabolites could similarly contribute to appetite suppression and weight regulation in the context of ketosis.
Through their experiments, the researchers discovered that BHB-amino acids not only suppress feeding behaviors but also promote weight loss, ultimately revealing a significant connection between ketosis and energy regulation. “This third, shunt pathway is vital for understanding appetite control and the weight loss typically associated with ketosis,” asserted Long.
Implications for Therapy and Research
Until this study, our fundamental understanding of ketosis was surprisingly incomplete,” observed Long. “Now, we are able to revisit various phenomena through this fresh perspective.”
For example, while the ketogenic diet’s efficacy in controlling seizures in children with drug-resistant epilepsy is well established, the broader impact—like enhancements in cognitive function or metabolic health—remains ambiguous, as does the underlying mechanisms. The discovery of these new metabolites provides a promising framework for systematically exploring these potential benefits.
What’s Next?
In fact, Long and his team are already revisiting the issue of epilepsy, with backing from the Wu Tsai Neurosciences Institute.
In a collaboration with Juliette Knowles, a clinical specialist in epilepsy at Stanford, Long aims to determine if the newly identified shunt pathway and its associated metabolites play a critical role in seizure management. If this proves true, it could pave the way for innovative treatments that emulate the benefits of ketosis without necessitating strict dietary adherence.
As the team delves deeper into the fundamental biology of ketosis, their findings hold the potential to revolutionize our understanding of its therapeutic capabilities—not only for epilepsy but also for various metabolic and neurological disorders.
“With enhanced insights into these pathways, we can formulate far more insightful inquiries regarding how and why these metabolites function, as well as what potential risks or constraints they may entail,” concluded Long.
Reference: Moya-Garzon MD, Wang M, Li VL, et al. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. Cell. 2024. doi: 10.1016/j.cell.2024.10.032
Ketosis: The New Highway to Health or Just Another Roadside Attraction?
Ah, the ketogenic diet. You’ve probably heard of it; it’s probably been offered to you by someone in a gym who swears it’s the holy grail of weight loss, paired with intermittent fasting. Let’s sum this up: the body flips a switch and starts burning fat instead of carbs. Simple, right? Well, not quite.
Now, before you go filling your fridge with bacon and avocados, enter Jonathan Long and his merry band of metabolic misfits, who are diving deep into the chemistry of ketones. You see, they’re not interested in the typical slap-and-tickle of ketogenic diet debates. Instead, they’ve rolled up their lab coats and waded into the ichthyological depths of metabolic pathways to find the elusive truth behind ketosis.
Shifting Gears: From Carbs to Ketones
When glucose—which sounds like something you’d add to your morning coffee—is out of the picture, the body takes a sharp turn. It starts breaking down fat and produces ketones, primarily beta-hydroxybutyrate (BHB). But hang on! Long isn’t convinced that ketones play by the same rules that we thought they did.
“Turns out,” he says, “ketosis isn’t a monolithic state.” It’s like trying to explain the complexity of a Game of Thrones character—sure, they may die, but there’s a whole season of other shenanigans first.
The new research from Long and company did something radical—they stepped back and decided to investigate the chemistry of ketones without cluttering their findings with the usual diet hype. Imagine being a kid in a candy store, but instead of sweets, you’re surrounded by mystical metabolic processes. Sounds far more fun!
Introducing the BHB-Amino Acid Concoction
During their research—so thrilling it rivals a Bond film—the team uncovered what they’re calling a “shunt pathway.” No, not a short cut you take to avoid traffic; we’re talking about a metabolic detour that could re-route the way we think about energy balance and appetite regulation. They discovered enzymes whimsically attaching BHB to amino acids, producing a funky family of compounds, adorably dubbed BHB-amino acids. Talk about a dinner party gone wild!
“So,” says Long, “imagine metabolic highways, and these shunts are like the quirky off-ramps. They might not be the main arteries but they lead you to unexpected and often fascinating places!”
Suppressing Appetite? Sign Me Up!
The real kicker? Long and his team found that these BHB-amino acids could suppress appetite and promote weight loss. Now, that’s exactly what we need—more science to back the notion that a craving for chocolate mousse is merely a figment of our sugary imagination. Wouldn’t it be lovely if we all had some BHB-amino magic to keep our palates at bay?
The Implications: More Than Just a Fad?
“So far, our understanding of ketosis was incomplete,” Long admits. And if you think about it, that’s akin to admitting you never grasped the plot of the movie Inception. It raises some serious questions about the ketogenic diet and its efficacy. Was it all just fancy food marketing, or are we on to something here?
One area that remains particularly tantalizing is the diet’s effectiveness in controlling seizures, especially in children with drug-resistant epilepsy. While we can throw carbs under the bus, there’s a lot more to be figured out about how these sporadic spikes in the BHB can lead to more than just an occasional loss of appetite.
What’s the Next Scoop?
With colleagues like Juliette Knowles in tow, Long is already putting the pedal to the metal, investigating the role of these metabolites in seizure control. Just picture it: a world where the benefits of ketosis can be enjoyed without the drudgery of a restrictive diet. That’s when your prayers of carbs and muffins will finally be answered!
Final Thoughts
As Long and his crew untangle the metabolic web of the ketone rave, we should expect a much clearer picture of how all this works. It’s like peeling an onion, only this time the layers might lead to the potential treatment for a host of metabolic and neurological conditions. Soon, we may find ourselves asking not just what we can eat but why our bodies behave the way that they do in the presence of these delightful little metabolites. Let’s hope they offer a feasible alternative to our beloved bread without the million-dollar gym membership!
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Said, reflecting on the potential implications of their findings. “With this new perspective, we can explore a variety of phenomena related to metabolic health and appetite control that were previously overlooked.”
This revelation about BHB-amino acids not only adds depth to our understanding of ketosis but also raises significant questions about the broader effects of the ketogenic diet. For instance, while it is well-known that ketogenic diets can effectively control seizures in children with drug-resistant epilepsy, the exact mechanisms through which they affect cognitive function and metabolic health remain murky. Long believes that identifying these new metabolites can help unravel these mysteries and lead to more targeted therapies.
In partnership with clinical experts like Juliette Knowles, Long’s team is set to investigate whether the shunt pathway and the newly identified metabolites impact seizure management directly. If they do, it could revolutionize treatment options, allowing patients to reap the benefits of ketosis without the rigid dietary restrictions that often accompany such protocols.
As they forge ahead with their research, Long and his colleagues are enthusiastic about the potential applications of their findings beyond epilepsy. With a better grasp of these metabolic pathways, they can tackle a variety of metabolic and neurological disorders. The hope is that with continued exploration, they will unveil actionable insights into how these metabolites contribute to energy regulation and appetite suppression, as well as discover any potential risks associated with their use.
while the ketogenic diet may seem like just another trending health fad, Long’s work suggests a much deeper and more complex reality. With a clearer understanding of how ketones function and their far-reaching implications, we might be on the brink of new therapeutic strategies that harness the power of ketosis in ways we never imagined before. Whether for weight loss, appetite control, cognitive enhancement, or even seizure management, the possibilities appear to be limitless, challenging us to reconsider our assumptions about diet, metabolism, and health in general.
**Reference**: Moya-Garzon MD, Wang M, Li VL, et al. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. *Cell*. 2024. doi: 10.1016/j.cell.2024.10.032
