ENP89: Brown Fat and Metabolic Function

Summary

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Episode Overview

Podcast: Endocrine News Podcast
Episode: ENP89: Brown Fat and Metabolic Function
Host: Aaron Lohr
Guest: Dr. Marcel Lino, Research Fellow at Joslin Diabetes Center
Date: August 21, 2024

In this episode, host Aaron Lohr interviews Dr. Marcel Lino about the latest findings on brown fat and its surprising roles in human metabolic function. Dr. Lino discusses new insights from his recent research on how brown fat communicates with other organs through exosomal microRNAs, potentially offering new avenues for metabolic disease therapies.

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Key Discussion Points and Insights

1. What is Brown Fat? (01:01)

• Brown fat is a specialized fat type found mainly in the back and subclavicular regions.
• Unlike white fat, which stores energy and is associated with obesity, brown fat burns energy—a process linked to better metabolic and cardiovascular health.
  • Dr. Lino: “Brown fat, once active, can actually expend vast amounts of energy and secrete a lot of factors that will improve your overall metabolic health...” (01:08)

2. Origin and Distribution of Brown Fat (01:29)

• Brown fat arises from a unique precursor, likely related to smooth muscle cells (Myf5 positive lineage).
• Humans have significantly less brown fat than rodents:
  • Infants have abundant brown fat; its quantity declines with age.
  • The physiological significance and health benefits persist even with less mass in adults.
• Studies link brown fat activity (not just quantity) to improved cardiometabolic outcomes in humans.
  • Dr. Lino: “Despite there being potentially less brown fat mass in humans than rodents, there was an association between brown fat activity and improved cardiometabolic outcomes.” (02:51)

3. Exosomes and Brown Fat Communication (04:01)

• Exosomes are small vesicles secreted by nearly all cells, but adipose tissue—especially brown fat—can increase exosome secretion when stimulated (by cold, drugs, possibly exercise).
• Exosomes can carry regulatory factors, notably microRNAs (miRNAs), which can influence distant organs’ metabolic functions.

4. Dr. Lino’s Study on Brown Fat and Exosomal microRNAs (05:10)

• Aim: Understand how brown fat regulates body-wide metabolism through mobile microRNAs, which act as endocrine signals.
• Key Method: Developed a method to label microRNAs derived specifically from brown fat, then trace their journey into other organs.
• Discovery: Brown fat–derived microRNAs are highly mobile, often enriching in specific organs.
  • Example: 31 unique microRNAs from brown fat preferentially accumulated in the hypothalamus (brain), largely bypassing the liver and muscle.
  • Dr. Lino: “We saw very robust labeling... micrornas were very good at transferring from brown fat to the liver, to the muscle, into the hypothalamus. ...31 micrornas...became specifically targeted to the hypothalamus.” (06:23)
• This suggests a targeting mechanism for microRNAs that’s not fully understood.

5. Innovative RNA Labeling Techniques (07:32)

• Technique: Genetically engineered mice express a bacterial enzyme only in brown fat. When fed a modified uracil, it incorporates into brown fat RNAs, uniquely marking them.
• This allows researchers to identify RNA molecules originating in brown fat in distant tissues.
  • “If it ends up into the rna, we can purify that rna. ...when we're detecting...in the brain and the liver, there was quite a lot of RNA that was labeled, even though the enzyme was not in those tissues, which told us that the RNA had to be coming from brown fat and ending up in those tissues.” (07:40)

6. Why Understanding microRNA Transport Matters (09:09)

• Knowing how and where microRNAs are produced and transported is vital for:
  • Moving beyond simple association studies or biomarkers.
  • Developing targeted RNA-based therapies for metabolic diseases.
• Without knowing the source and target, it's hard to translate findings into therapeutics.
  • Dr. Lino: “If you don't know where it is originating from and where it is acting on, it makes it difficult to extend it beyond the biomarker stage into something that's more therapeutic.” (09:53)
• The “holy grail” is figuring out how to deliver microRNAs specifically to tissues that need them.

7. Clinical Implications and Future Directions (11:07)

• RNA-based therapies could revolutionize endocrine and metabolic disease management due to high specificity and tunability.
• Learning how microRNAs target organs may drastically improve drug design and delivery systems.
  • “If we can figure some of this information out, it can give us a lot of new tools that we can use in the drug design pipeline...” (12:13)

8. Dr. Lino’s Personal and Research Future (12:45)

• Dr. Lino is focused on concluding and publishing current research.
• Long-term aspirations include running his own lab to continue this line of investigation, though he's open to evolutionary shifts in his career path.
  • “I think there are sometimes when you’re doing something that’s so exciting for you...you tend to forget [plans].” (12:54)

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Notable Quotes & Memorable Moments

• Dr. Lino, on new findings:
  “Some of these micrornas…actually tended to become enriched in specific organs—for example, the hypothalamus…despite the fact that they all originated from brown fat…So it seems like there is a targeting mechanism here that we don’t understand.” (06:40)

• On the importance of source-target identification:
  “If you wanted to, for say, say, okay, let. Seven is an important. Micro RNA has been implicated in obesity. Is it beneficial in some organs and detrimental to some others, and which organ is making it? …The biggest challenge, of course, sort of holy grail…being, can I get it there and deliver it there specifically?” (10:42)

• On RNA-based therapies:
  “They present a unique and very powerful opportunity to make specialized medicines, not only because they're very tunable from individual to individual, but ...the actual nucleotide sequence itself is very specific and encodes a lot of information in a very small space.” (11:14)

• Career reflections:
  “If I were to say right now I’d like to have my own lab in the future...but if I go back 10 years, I don’t think I would have envisioned being where I am now. So why limit myself to saying this is what I'm going to do. And who knows?” (13:29)

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Episode Timeline

| Timestamp | Segment | |-----------|-----------------------------------------------------------------| | 00:00 | Intro: Brown fat and metabolic function | | 01:01 | What is brown fat? | | 01:29 | Origins and comparative biology (humans vs. mice) | | 03:52 | Exosomes and their connections to brown fat | | 05:10 | Dr. Lino’s recent study: Methods and discoveries | | 07:32 | Innovative RNA labeling tool | | 09:09 | Why tissue-to-tissue microRNA transport matters | | 10:52 | Potential for clinical impact, RNA therapies | | 12:45 | Dr. Lino’s personal future and research ambitions |

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Conclusion

This episode offers a deep dive into the cutting edge of brown fat research, particularly focusing on how brown fat may be communicating across organs through exosomal microRNAs. Dr. Lino’s discoveries open important new questions about tissue signaling and the future of RNA-based therapies—a field poised for major advances in personalized metabolic medicine.

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Transcript

[A]

Hello, I'm Aaron Lohr, and this is the Endocrine News Podcast. Today we're talking about brown fat and some new discoveries in how it regulates metabolic function. And can't wait to hear about this. And joining me today is Dr. Marcel Lino, a research fellow at Joslin Diabetes Center. Dr. Lino recently presented an abstract at Endo 2024 entitled A New Layer of Endocrine Brown fat secretes exosomal micrornas, which regulate metabolic functions in distal organs. Thank you for being here today.

[B]

Well, thank you for having me here today and giving me an opportunity to discuss my research.

[C]

Great.

[A]

I'm looking forward to hearing about this. So, first, what is brown fat and what do we know about how it impacts our health?

[B]

So, brown fat is this subtype of fat that's typically found in the back and subclavicular regions of the body, and it has this unique ability to expend energy. So whereas most of the fat in your body will store energy and has been associated with obesity and disease, brown fat, once active, can actually expend vast amounts of energy and secrete a lot of factors that will improve your overall metabolic health and have been linked to improved cardiovascular outcomes as well.

[A]

Where does brown fat come from? Is it something that's easily gained or that we can build?

[B]

So that's an interesting question, and one that a lot of labs are dedicating their careers to to try to figure out the origins of brown fat on a cellular level. There's studies that support the origin of brown fat as a common progenitor, originated from an earlier cell lineage that's shared with smooth muscle cells. Think they are Myth 5 positive cells that give rise to brown fat at unique locations in the body. Most of these have been studied in mice, of course, where there is a lot more brown fat than there is in humans. In mice, we typically will find it in the subclavicular region and the subscapular area in the back, whereas in humans, there's a lot less of it in the subscapular area. In adults, it's much more abundant in infants. So after birth. But then as we age, we tend to lose the brown fat mass, which is a bit of an interesting consideration to make because sometimes it looks like what we find in mice doesn't translate in human. And this is one of those where humans don't necessarily have as much brown fat as mice. There was a study by Paul Cohen just a few years ago that looked at massive retrospective cohort. They assessed the association of brown fat in patients with Their cardiovascular outcomes and what they showed very clearly that despite there being potentially less brown fat mass in humans and rodents, there was an association between brown fat activity and improved cardiometabolic outcomes. There is a metabolic benefit exerted from brown fat. But what we don't know quite as well in humans as we do in mice is how to really increase the mass of a brown fat. There are several drugs that have been developed that can induce brown fat. Ground trial comes to mind. And there are clear benefits to brown fat induction, whether pharmacologically or by cold exposure as well. But we don't have as much as we do the other fat depots. But a lot of work is still ongoing and figuring out which brown fat depots in the human body are more metabolically beneficial. For example, we have deep neck fat. A colleague of mine presented as well to show some interesting findings there. And there are areas of the body that have brown fat, but we don't know much about how they differ among each other. And comparing it to mouse.

[A]

Your study also looks at exosomes. I know they're somehow related to brown fat, so why don't you tell us a little about that? Why are exosomes important? How are they connected to brown fat?

[B]

So exosomes, they're these tiny little vesicles secreted by almost every cell type in the body. But the fat, our research has shown in the past secretes a lot more vesicles than other tissues. And the brown fat is very special in the sense that it'll secrete vesicles, but that can be turned up to secrete even more when it is stimulated. And when I say stimulated, there are two known ways that we can stimulate a brown fat in both rodents as well as in humans, and that is either by cold exposure or beta adrenergic receptor agonism, or maybe sometimes exercise, depending on the stimulus that will cause brown fat to secrete more of these exosomes or extracellular vesicles. And this is an important piece of this study because the exosomes are thought to carry a lot of important factors that include endocrine factors as well as micrornas, which I'm studying here today.

[A]

Well, why don't we jump into it a little bit? So you did present a study at Endo 2024. It's about brief brown fat. It's about brown fat and exosomal micrornas. And what did you hope to learn in this study?

[B]

What we're hoping to learn is primarily how brown fat is regulating your overall metabolism and health. And the reason we're focused on micrornas and have been focused for some time, is because they're very understudied rna, especially in the context of endocrine regulation. So previous work from our lab has shown that micrornas are very mobile, contrary to other RNAs that are made in one tissue, and they stay there. And part of how they are transferred from brown fat to other organs is these exosomes. And since their main function is to bind to and suppress the translation of target genes, they have the potential to act as endocrine regulators at a long range. And so we thought, okay, what if we had a model where we can label the RNA the brown fat specifically, and by labeling it only the brown fat, can we detect it in the circulation? Can we detect it in the liver, the muscle, and even the hypothalamus? And we did find some very interesting results here where we saw very robust labeling of all kinds of RNAs in the brown fat. But specifically, micrornas were very good at transferring from brown fat to the liver, to the muscle into the hypothalamus. In with that came probably the most unexpected finding in my work, which showed that some of these micrornas, or a lot of them, actually tended to become enriched in specific organs. For example, the hypothalamus. We saw 31 micrornas that became specifically targeted to the hypothalamus. Now, this is despite the fact that they all originated from brown fat and may have been secreted by different carriers. So some of them were in exosomes, some of them were in other plasma fractions that are more associated with protein. So we don't know yet, but sure hope to find out for the next little bit how this is regulated, because those micrornas that became enriched in the hypothalamus seem to almost entirely miss the liver and the muscle. So it seems like there is a targeting mechanism here that we don't understand. But because we have this new tool to track the RNA transfer, we think we might be able to get to the bottom of at least a little bit of it, which could have a massive impact.

[A]

Well, it's always exciting to know what the next great thing to the research is. You know, good research will unlock potential for more. But this tool you talked a little bit about, can you tell us more about what you use and what this tool is?

[B]

It's an RNA labeling technique that's been described about 15 years ago, perhaps even earlier than that, but it was used in mice where you can introduce a modified nucleotide, in this case, it's 4th uracil. And because it's modified chemically, we can detect it, we can purify it. So if it ends up into the rna, we can purify that rna. But in order for it to be incorporated into rna, it requires an enzyme that is not active in mice. So we have this model where this enzyme that comes from a bacterial organism can be transgenically introduced into the mice and be specifically expressed only in your tissue of choice. And in this case, we chose the brown fat because of its health benefits and the fact that it's known to secrete micrornas. So when we express this enzyme only in the brown fat and we introduce the modified nucleotide into the circulation, the brown fat RNAs are the only RNAs that can incorporate this modified nucleotide into their RNA. So then when we're detecting, in the case of the brain and the liver, there was quite a lot of RNA that was labeled, even though the enzyme was not in those tissues, which told us that the RNA had to be coming from brown fat and ending up in those tissues. So this tool was adapted to this particular question because usually it's just been used to label RNA in one specific organ and see the metabolic labeling or sort of the decay rate of RNAs, so you can measure how fast an RNA is made or decays in that organ. But we said, well, can we use this to track what's coming from that organ in another organ that does not express the enzyme? And so we're happy to get that to work about a year ago and not start getting some meaningful results.

[A]

That is exciting and just for our listeners so we can make sure that they fully embrace and share our excitement. Why is it so important to get a good understanding of how micrornas can transfer between tissues and organs? Why is that dynamic so important for us to get a better understanding of?

[B]

I think there's two things that come from getting a better understanding of micrornas, or in general, any factor that's secreted from one organ and accumulates in another organ. When we look at micrornas in, say, human studies, a lot of work has been done to identify micrornas that are associated with obesity, with brown fat activity, with exercise, healthy and unhealthy phenotypes. There was a study recently that looked at micrornas. Even in some of the Boston Marathon runners. We can see different factors that are associated with improved health. Now, that is all interesting as long as we know that they are being Made in one place. But if they are so mobile, knowing what's in the blood only tells you part of the story. So it's kind of an association at best. But if you don't know where it is originating from and where it is acting on it, makes it difficult to extend it beyond the biomarker stage into something that's more therapeutic. So if you wanted to, for say, say, okay, let. Seven is an important. Micro RNA has been implicated in obesity. Is it beneficial in some organs and detrimental to some others, and which organ is making it? And if we know this information, we can say, okay, we know that in this particular context and in this particular organ, this microrna can exert a benefit. The biggest challenge, of course, sort of holy grail of any of these therapies being, can I get it there and deliver it there specifically?

[A]

I know it's probably still years away, but when you think for the future how your research might inspire, you know, maybe some changes in clinical care and what some of these therapeutic targets might be, you know, what do you think might be some options?

[B]

I think we're entering an age where RNA based therapies are becoming more and more accepted, not only by the public, but also entering more and more into clinical trials. And they present a unique and very powerful opportunity to make specialized medicines, not only because they're very tunable from individual to individual, but. But the actual nucleotide sequence itself is very specific and encodes a lot of information in a very small space. This is what nucleotides have specialized to do. So if we're able to harness that and understand how is it that the body knows where these micrornas are supposed to go, that would be an incredible achievement which may well never be accomplished. But if in any way this work can give us even a little bit of a hint for how some micrornas may end up in one organ compared to another, even though they came from the same source, whether that is because they are loaded into different carriers, maybe it's the exosomes. Maybe the exosomes have something on their surface that makes them easier to uptake in the liver compared to another tissue. If we can figure some of this information out, it can give us a lot of new tools that we can use in the drug design pipeline, which I think will probably have the biggest impact there.

[A]

That does sound exciting. All right, so last question. What's next for you? There's a lot here, obviously, that needs to be looked at, but when you think about where you want to focus some of your energy and research for the next three to five years or so. Where do you want to focus?

[B]

That's an excellent question that my parents and everyone else, everyone else is asking, what are you going to do next? And I never thought I'd say this because I entered into my fellowship saying that, yep, this is what I'm going to do. And in X amount of time I'm going to be at this stage or I'm going home or I'm going to this place. But I think there are some times when you're doing something that's so exciting for you or it really captivates you, you tend to forget that. So I am not sure where it's going to go, to be honest. I think right now I'm really engrossed in trying to finish this work and getting it published, which is pretty soon. Once that's done, I'll turn my focus on what's next. And I'm lucky to have a great mentor that does a lot of that for me. He has this plan where he thinks I can end up in order to encourage me to progress my career. If I, if I were to say right now I'd like to have my own lab in the future where wonderful doing this kind of work, but if I go back 10 years, I don't think I would have envisioned being where I am now. So why limit myself to saying this is what I'm going to do. And who knows?

[A]

That sounds like a super healthy outlook. And if you continue on this path and you have some more work in here that you'd want to make sure you share with others, I would love to have you back on the podcast to hear how much this, this field is growing.

[B]

Yeah, I'd love to be back and hopefully I can be back with something new.

[A]

Wonderful.

[C]

And that's all for this episode. I hope you enjoyed my conversation with Dr. Lino and learning more about about brown fat and how it regulates metabolic function. Before we go, I want to let you know about an exciting new event that you may want to check out. The Endocrine Society's AI and Healthcare Virtual Summit is coming November 8th and 9th, 2024. It's an innovative two day virtual event designed to inform providers, healthcare professionals, researchers, technologists, industry stakeholders and educators on the capabilities of artificial intelligence in the healthcare field. This summit offers a unique opportunity to delve into the transformative potential of AI and revolutionizing patient care and shaping the future of medicine. If you want to discover how AI technologies are redefining diagnostics, treatment planning and patient outcomes in healthcare and explore the latest advancements in predictive analytics and machine learning algorithms. This event is for you. We'll provide a link to it in today's episode description and until next time, thanks for listening.

[A]

Endocrine News Podcasts are a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.