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Voiceover
Welcome to Beyond Lab Walls, a podcast from the Salk Institute. Join hosts Isabella Davis and Nicole Mlynaryk on a journey behind the scenes of the renowned Research institute in San Diego, California. We’re taking you inside the lab to hear the latest discoveries and cutting-edge neuroscience, plant biology, cancer, aging, and more. Explore the fascinating world of science while listening to the stories of the brilliant minds behind it.
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Voiceover
Here at Salk, we’re unlocking the secrets of life itself and sharing them beyond lab walls.
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Nicole Mlynaryk
Hi, everyone. Welcome back to Beyond Lab Walls. I’m your co-host, Nicole, and in this episode, we’re exploring the science of a hot topic: GLP-1 weight loss drugs. These blockbuster drugs have totally changed the way we understand and treat obesity. But where do they come from and where are they going? What are their biggest strengths, and what are their current shortcomings?
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Nicole Mlynaryk
And how is Salk science contributing to all of this? We sat down with Salk scientist Christian Metallo to hear all about how he and his peers are thinking about these drugs, and how his research could help improve these and other weight loss treatments in the near future. But before we dive into the science, I just want to set the scene a little.
00;01;40;14 – 00;02;09;04
Nicole Mlynaryk
Let’s quickly remind ourselves what these drugs are and how they came to be. When Ozempic was first approved by the FDA in 2017, it was designed to treat type two diabetes. The drug is basically a synthetic version of a natural hormone that activates the GLP-1 receptor in our gut. When these receptors are activated, they trigger a whole cascade of molecular signals throughout the body that are normally activated after we eat.
00;02;09;07 – 00;02;31;11
Nicole Mlynaryk
So, for example, the pancreas starts to release more insulin to help control our blood sugar levels. Other signals get sent to our brain to tell us that we’re feeling full, so we can be less motivated to keep eating. The drug was super effective in helping people with diabetes regulate their blood sugar, but it wasn’t long before doctors realized it was also supporting significant weight loss.
00;02;31;16 – 00;02;54;16
Nicole Mlynaryk
Once further clinical trials confirmed those effects, the drug was officially approved for the treatment of obesity in 2021 under the brand name Wegovy. Other variations of these drugs quickly followed, so that’s where we got all these new versions, like Mounjaro, Zepbound, and Trulicity. Many of these newer drugs target not only the GLP-1 receptor, but also other similar receptors.
00;02;54;18 – 00;03;28;23
Nicole Mlynaryk
This whole family of molecular receptors responds to a class of hormones called incretins, which basically exist to facilitate digestion. They help our bodies absorb and metabolize our food. But in diseases like diabetes or obesity, these molecular pathways can malfunction. So it’s really exciting that we’re finding all these new ways to target these processes with new treatments and help them get back on track.
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Nicole Mlynaryk
But with all these new medications suddenly coming out in quick succession, it’s important to remember that these sorts of miracle drugs don’t just appear out of thin air. Scientists and clinicians have been studying digestion and metabolism for centuries. The concept of incretin hormones was first described in the early 1900s, and GLP-1 wasn’t discovered until the 1980s. Even now, our understanding of the biology of metabolism is very much still evolving.
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Nicole Mlynaryk
But it’s this kind of foundational science research that enables the miracle drugs of the future. So here we are at the dawn of a new era in weight loss treatment. But where will things go from here? And what do we still have left to learn? To answer those questions, I turn to Salk scientist Christian Martello. Christian is a chemical engineer by training.
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Nicole Mlynaryk
He sees our tissues and organs as a series of inputs and outputs, where certain molecules go in, and different molecules go out. He’s asking fundamental questions like how do the sugars, fats, and proteins we take in through our diet get metabolized by our cells and transformed into more usable forms of energy?
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克里斯蒂安·梅塔洛
GLP drugs mimic metabolic hormones. So just like insulin is a hormone that regulates our response to glucose, GLPs are incretins. They’re hormones that communicate from our gut to our brain to regulate how much we eat and our desire to eat. Their main strength is that they simply work. They work effectively to curb eating in patients, and we have decades of evidence with the obesity epidemic that gaining too much weight and eating too much comes with a number of different comorbidities that shorten lifespan quite a bit.
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克里斯蒂安·梅塔洛
So by reducing food intake in patients, patients lose weight. And we’re seeing these tremendous benefits. You put less pressure on your joints. There’s less stress on your heart. You’re metabolically improved. You can see better cognition in some ways because you’re in more of a fasting-type state.
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Nicole Mlynaryk
As more people try GLP-1 drugs, clinicians are hearing all sorts of anecdotal evidence of other positive side effects. And that’s all super interesting and exciting data to follow up on. On the other hand, though, we are noticing some examples of potential negative side effects, which also need to be further explored and addressed.
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克里斯蒂安·梅塔洛
So one of the biggest weaknesses is concern for muscle loss and loss of muscle mass. While these drugs work, in the end, thermodynamics wins out, and the energy needs to come from somewhere. So as patients eat less or they forget to eat, the body responds and you still need to generate energy and make glucose to feed the brain and other tissues.
00;06;27;19 – 00;06;56;09
克里斯蒂安·梅塔洛
So one of the ways the body does that is by degrading muscle and converting muscle into energy that feeds the other tissues. So that loss of muscle mass can reduce patient strength and coordination. That is one of the major factors causing age-associated morbidities, loss of muscle mass. So as patients age you want to retain that strength.
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克里斯蒂安·梅塔洛
So the big balancing act is loss of fat versus loss of muscle. Fat is mostly carbon. It’s an energy storage and it’s actually fairly easy to make. Muscle is enriched in protein. And the way to think about the differences between fat and muscle is the protein. To synthesize new protein, you need a full complement of all 21 amino acids, plus a plethora of other nutrients.
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克里斯蒂安·梅塔洛
You also need time and resistance training, and that’s some of the things that people do to combat these side effects, incorporating resistance training and making sure you’re taking in enough amino acids and other nutrients to make sure that the patients are building muscle or maintaining muscle mass and predominantly losing fat mass.
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克里斯蒂安·梅塔洛
So the next generation drugs are going to start to modulate how muscle responds to these starvation signals to try to limit muscle loss.
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Nicole Mlynaryk
So how are Christian and other scientists at Salk tackling this problem? How can learning more about the biology of metabolism help us treat and prevent these harmful side effects?
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克里斯蒂安·梅塔洛
My laboratory aims to understand how metabolic pathways become dysregulated in different diseases, ranging from cancer to neurodegeneration to metabolic syndrome. Metabolic pathways are the molecular steps through which we use to convert nutrients to energy, or to convert nutrients to muscle for regenerative purposes. So it’s those step-by-step chemical reactions. The pathways are the multitude of chemical reactions all working together, in the same way that we breathe in oxygen and breathe out CO2, those are metabolic pathways working.
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克里斯蒂安·梅塔洛
Our knowledge of the architecture of most metabolic pathways has come from reaction-by-reaction, painstaking studies over the last 50 years. And what’s happened in the last few decades is there’s been tremendous advances in technology that allow us to visualize and observe each molecule in the system, and that’s allowed us to build more collective models that encompass pathways in their entirety, either at a cellular level, at a tissue level, or an organismal level.
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克里斯蒂安·梅塔洛
On top of that, the discovery of hormones beyond insulin, beyond glucagon, which includes the incretins, has identified other control points that have now been worked on over the course of decades to turn into these great therapies.
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Nicole Mlynaryk
Christian’s lab is a leader in one of these newest techniques called metabolic flux analysis, which combines the latest genetic and biochemistry techniques with engineering principles like fluid dynamics. In many of their experiments, they use what they call “tracer nutrients,” which are basically molecules you would find in food, but they’re a little bit heavier on a molecular level, and that allows the researchers to find them and track them as the body is metabolizing them.
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Nicole Mlynaryk
That’s done using state-of-the-art metabolomics and mass spectrometry tools, which tell the scientists exactly what molecules the tracer nutrients are getting turned into. Christian and his team then perform flux analysis on this data, which boils down to a lot of math, and then that lets them compare the flow, or the rate of movement of each of these molecules in different organs, metabolic stages, disease states, and so on.
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Nicole Mlynaryk
And through this process, they discover new important pathways, and they find opportunities to create more effective therapeutic interventions for metabolic disorders.
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克里斯蒂安·梅塔洛
So we have a number of different projects that link to and may advance or improve incretin-based therapies. We study how different fats are metabolized in the liver or in adipose tissue, in fat tissue, and try to understand how they work as signaling molecules to improve our metabolism. We also have other lines of research exploring how the body regulates amino acid maintenance. The amino acids are the precursors and building blocks for proteins which are highly enriched in muscle. And by studying diseases or conditions that are marked by low amino acid levels and replenishing those, or inhibiting those enzymes that degrade specific amino acids,
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克里斯蒂安·梅塔洛
We start to see improvements in neurological functions in the peripheral nervous system, in wound healing and muscle regeneration. We’re particularly focused on a combination of amino acids, serine, glycine, and threonine, that are altered in the context of aging, in the context of diabetes, and obesity. And we’re working to develop therapies and other strategies that may augment the levels of amino acids in patients as they age or as they experience diabetes symptoms.
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克里斯蒂安·梅塔洛
Importantly, incretins, in inducing that starvation signal, will activate the pathways that are important to degrade those amino acids. So by blocking those specific steps, we’re hoping that they may improve age and diabetes and obesity-associated defects in wound healing and in nervous system function. We’re still at the early stage in some of these questions, but they could turn into medications that are added on top of GLPs.
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克里斯蒂安·梅塔洛
At the same time, companies are working to improve their function with next-generation incretins or combination therapies that may stave off muscle loss, as well.
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Nicole Mlynaryk
Several labs that Salk are currently working on exactly that, studying this interaction between gut hormones and muscle regulation. Ron Evans’ lab, for example, recently discovered a set of molecules that are super important for maintaining muscle mass during periods of fasting. They’re currently exploring ways to activate this pathway, centered around a hormone receptor called BCL6. They say future weight loss treatments could potentially combine GLP-1 drugs with a second medication to activate this pathway and help maintain patients’ muscle mass while they’re losing weight.
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克里斯蒂安·梅塔洛
I think there’s never going to be a wonder drug that just fixes all of these problems. The old adage is no pain, no gain. And this phenomenon that we’re discussing about loss of muscle and the difficulty in keeping weight down, fat weight down, and retaining muscle, also occurs when you’re dieting. If you experience that yo-yo effect, losing weight and regaining weight because it’s easier to make fat than it is to make muscle.
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克里斯蒂安·梅塔洛
You see this shift, and you start to gain more fat mass at the loss of muscle mass. In any of these strategies, not only is it going to be taking a new drug, but it’s maintaining resistance training to maintain that muscle mass. Watching what you eat. There’s no cure-all that fixes poor nutrition intake. So all of these therapies need to be combined with effective dietary changes and resistance training to improve your overall health.
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Nicole Mlynaryk
Christian points out an important idea. Metabolism is complex, but at its core, it’s about how our cells convert one set of molecules into another to make, store, or use energy. And the more healthy and efficient those processes, the better our entire body functions. In fact, we’re already seeing plenty of examples where GLP-1 drugs seem to be supporting other aspects of patients’ health, from supporting heart health to improving mental clarity.
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Nicole Mlynaryk
So how will studying the basic mechanisms of metabolism continue to inform our treatment of other health conditions, besides obesity and weight management?
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克里斯蒂安·梅塔洛
There are molecular changes in metabolism that occur in virtually any disease, and they’re often impacted by altering our nutrient intake. So the techniques that we apply here at Salk are really allowing us to map the metabolic changes that occur in these different disease contexts. Metabolism occurs in every tissue of our body, and it’s dysregulated in almost every disease.
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克里斯蒂安·梅塔洛
So there’s tremendous opportunities for us to harness this information to better understand simply how our tissues function and how they get broken down in the context of disease. In some contexts, when we’re not studying weight management in the context of obesity, we can take patient tumor cells or patient tumors and feed them labeled nutrients and see exactly how a patient’s tumor is metabolizing the surrounding nutrients.
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克里斯蒂安·梅塔洛
And we can do that with patients with tumors with different genetic backgrounds. So we can better understand how the genetic makeup of a specific patient’s tumor might dictate how it metabolizes nutrients, and how it might be better targeted in a therapeutic sense.
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Nicole Mlynaryk
Christian is also applying this approach to Salk’s Year of Brain Health. The Institute has now launched a major campaign to support and advance our research on brain health, and understanding how cellular metabolism supports a well-fueled and high-functioning brain is a central pillar of this research program. So, what does Christian think about how GLP one drugs will factor into the future of brain health?
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克里斯蒂安·梅塔洛
Well, I think at the moment we just understand that there are benefits to having improved overall metabolic function. This can improve vascular function function so you get improved blood flow to different organs. At the same time, these incretin drugs can induce brain fog if people forget to eat and don’t eat enough. That anecdotally observed as well. But this brings us to this new appreciation that we’re having about the importance of metabolism in all tissues.
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克里斯蒂安·梅塔洛
And by gaining a better molecular understanding and mapping how different nutrients feed different tissues or even different parts of the brain, we’re gaining a much better appreciation, and we’re starting to discover new ways of influencing brain function and brain health.
00;18;27;06 – 00;18;52;19
Nicole Mlynaryk
We’re really entering a new chapter in our understanding of metabolism and weight regulation, and how these processes shape other parts of our health and our ability to fight disease. It’s an exciting time, but we also appreciate that in many ways it’s kind of a confusing time. We’re learning more and more about nutrition and metabolism at a faster pace than ever, and the biology is complex, so the answers aren’t always straightforward.
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Nicole Mlynaryk
But in time and with more data, we learn, and the science solidifies. GLP-1 drugs didn’t come out of nowhere. They’re the result of decades of painstaking research, and there are still a lot of questions left to be answered. But we’re doing it. And one day soon we’ll all be better for it.
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Nicole Mlynaryk
If you’d like to learn more about how Salk scientists are influencing the future of weight loss treatments, or you want to support any of our research on metabolism, cancer, brain health, and more, please visit salk.edu. That’s Salk.edu. Sign up for our newsletter while you’re there, and follow us on socials to get the latest updates on what Christian and his collaborators are up to at the Institute.
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Nicole Mlynaryk
Until next time, thanks for listening to Beyond Lab Walls.
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Voiceover
Beyond Lab Walls is a production of the Salk Office of Communications. To hear the latest science stories coming out of Salk, subscribe to our podcast and visit Salk.edu to join our new exclusive media channel, Salk Streaming. There you’ll find interviews with our scientists, videos on our recent studies, and public lectures by our world-renowned professors. You can also explore our award-winning magazine, Inside Salk, and join our monthly newsletter to stay up to date on the world within these walls.