GLP-1s and mitochondrial function
GLP-1 medications like Ozempic and Wegovy are everywhere right now, but what are they actually doing to your mitochondria? In this episode, Georgia Truman sits down with MitoQ CSO Dr. Siobhan Mitchell to unpack the science behind GLP-1 agonists, from appetite suppression and insulin sensitivity to the less-talked-about effects on muscle loss, dopamine, and metabolic "reset" after coming off the medication.
They cover:
Why obesity changes mitochondrial function at the cellular level
How GLP-1s can boost mitochondrial biogenesis and reduce oxidative stress
The real story behind muscle loss on GLP-1s (and how much comes down to protein intake)
What's happening in the brain - dopamine, motivation, and the "Ozempic personality" conversation
Practical nutrition and supplement strategies to protect muscle and mitochondrial health while on and after a GLP-1
Whether you're on a GLP-1, considering one, or just curious about the mitochondrial science behind the headlines, this episode goes well beyond the appetite-suppression story.
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Georgia (00:16)
Welcome back to the MitoPod. My name is Georgia Truman, and I am the Scientific Affairs Manager for the MCRP. You can find us at mitoquinol.org. ⁓ I am joined again by Dr. Siobhan Mitchell. She is the CSO of MitoQ and she is our in-house mitochondrial expert and neuroscientist. We are here talking today about GLP1s, not just their mechanisms and what they do, but specifically looking at mitochondrials.
How they might be impacting mitochondria health. So thank you so much, Dr. Siobhan for coming back and chatting to me today.
Siobhan (00:54)
Yeah, I have to say I'm really excited by this conversation. I love talking about GLP1s and I think that area of how they're affecting mitochondria has not been talked about enough. So happy to just dive in and go crazy.
Georgia (01:08)
Yeah, absolutely.
I was looking up this morning and I read some statistics. So that twelve percent of Americans are either on a GLP one or they have been on a GLP one, ⁓ and six percent are currently taking one. So I knew that these medications were popular, but I don't think I realised ⁓ quite how popular they are. So I'm excited to talk about mitochondria because I think it will be applicable for ⁓ quite a few people. ⁓ I think we'll start off by kind of getting into
What GLP1 medications are and what they're targeting. So maybe if you could just take us through some basics about GLP1s.
Siobhan (01:46)
Okay, I will be brief because I feel like this has been discussed a lot, but the main gist is that GLP1 peptides are a natural peptide in our bodies that help control our postprandial response. And when I say postprandial, that sounds like, what are you talking about? I'm just talking about like how we respond after a meal. And this is particularly important because GLP1s, I think everyone's heard.
That they can suppress appetite. And so that's one thing they're doing. But then they're also helping modulate our insulin and glucose responses to that meal. And that's even more important and I think really relevant for the mitochondria discussion we're going to have. So yeah, GLP1s are secreted mainly, yeah, like to get your body ready to process all this fuel that you've just had after a meal.
The thing I want to make sure everyone is aware of is a GLP-1 peptide, your natural peptide, is only going to be around for like a few minutes. So you eat, you know, a bunch of fat or you know a meal, I should say, and then you will have the GLP1s released, especially when you're making short-chain fatty acids by your microbiome, or glucose or other things, but but especially if with short-chain fatty acids, and then the GLP1s.
After a while, they are broken down by DPP4, which is yeah, basically just this breakdown enzyme, and then that's it. And then your appetite kind of comes back and all the rest. What's interesting about GLP1 medications is these are GLP1 agonists. So they're affecting the GLP1 receptor, and they're designed to be long-lasting. So they stick around for a very long time. So you're getting that appetite suppression, you're getting that kind of more I would say sensitive insulin sort of response and more glucose kind of being sequestered. And this is where I would say, you know, the big difference lies. And yeah, we'll we'll get into that more, I think.
Georgia (03:54)
Cool. So it's taking advantage of a natural mechanism that we already have, just making it last longer.
Siobhan (04:00)
last longer exactly. Because I think that's the big trick is is just making it so that yeah, your body wants to kind of like get rid of that response pretty quickly and kind of bring you back to a kind of homeostasis. But with the GLP one agonists, they're kind of preventing that from happening. So yeah, and this is this is part of the problem is we're gonna talk about later is sometimes it's good to be hungry, sometimes it's good to wanna eat food. And so
Georgia (04:25)
Yeah.
Siobhan (04:27)
The thing that people often experience is that they literally just don't want to eat food anymore when they've had a high enough GLP one agonist dose.
Georgia (04:32)
Mm-hmm.
Mm-hmm. I guess it makes finding the right dose for you really important.
Siobhan (04:40)
Yeah, exactly. And this is where I I also don't want to go into all this, but GLP ones, because of the fact that they slow down on your gut, kind of, you know, in terms of the muscles in your gut that are helping get food through you and then also controlling some of the sort of satiation signals of your gut. When you take too much, that's when you start to get that nausea and that feeling of like I am really full, I feel gross. So yeah, that's the other thing that that can happen when you have too much.
Georgia (05:02)
⁓
Yeah.
Okay. So I have heard that some medication some GLP one medications I should say maybe cause more nausea than others. So there are different types of GLP one medication. Are you able to go into some of the differences between them?
Siobhan (05:25)
my gosh, there are so many differences. I I think we could just take the whole podcast going to some of the developments that are going on right now. I would say what I can tell you is that the early GLP1 agonists had a lot more nausea because they were not, I would say, kind of potent on just the GLP1 receptor. And yeah, it was hard to kind of control the potency of it, so they were much more nauseating.
Georgia (05:29)
Okay.
Siobhan (05:54)
For instance, litroglutide, semiglutide, the kind of really popular one right now, Ozempic it's also called Wegovy. This one is a little less nausea, and I understand the ones coming up. So there's a whole bunch of sort of second and third generations trazepidide. And then one that's really popular right now. It's not got released yet, but everyone's really excited by it. retatrutide This is another GLP one.
Agonist that also does a bunch of other things. So it, for instance, helps with glucagon regulation as well, too. And it also affects ⁓ another kind of peptide that's very important for, I would say, metabolism called GIP1, which I'm I'm not going to go into all the sort of things that they're doing. But what is interesting is that these second and third tier ones are not so potent at the GLP one.
Agonism, they're kind of doing other stuff as well, so you don't have to get as much nausea.
Georgia (06:57)
so you mentioned DPP four which breaks down GLP ones. Is there a medication that is coming out or already released that works on that mechanism as well?
Siobhan (07:06)
Yeah, yeah, there there are ones that are already ⁓ there is like standalone, for instance. and just so I should preface DPP four stands for dipeptidal peptidase. Don't remember that, you don't need to. Just remember DPP four. Th there are already standalone medications that just work on that alone. But yeah, it's very popular now to combine it with ⁓ a GLP one agonist. So yeah, this is this is one of the secrets. But
Georgia (07:27)
Okay.
Okay.
Siobhan (07:36)
I would say the big secret right now is that they're now having these pills. So normally Ozempic, Wegovy, all these others are something you have to inject, and a lot of people don't like to inject themselves. The big difference is now that you can actually take some of these peptides orally and get the same effect or or at least moderately the same effect.
Georgia (07:56)
Okay, so I wanted to jump
kind of straight into mitochondria and how GLP1s might be impacting mitochondria function, for better or for worse, I'm sure you're gonna tell me. But I wanted to start with maybe looking at mitochondria, maybe in someone who is of a normal weight and if there are any differences between mitochondria of healthy individuals or individuals with obesity or individuals who are overweight.
Siobhan (08:22)
Yeah, this is a really interesting area because there has been a lot understood about how obesity affects mitochondria. And in fact, very much so your mitochondria are affected. So I'm gonna start off with the fat cells. So fat cells of obese people mostly look bigger than people who are not overweight. So this is where as you get more and more overweight.
You have this kind of hypertrophy of your adipose tissue or your adipose cells, so they just get bigger and bigger as they expand in terms of you know just more fat storage and lipid droplets. So this can be an issue because basically, one, you're kind of making it so these huge cells are no longer getting the blood supply that they need and also the oxygen they need, so they're not getting as much nutrients. And so things like oxygen, which you need to have.
mitochondrial function, oxidative phosphorylation is not being done as well. And so this is where there's I would say kind of two different stages of being overweight. the fact that you are having people take in so many calories, so much sugar and fat that your mitochondria and your fat cells and kind of everywhere else are
Getting too much energy, and so your mitochondria to deal with all this, glucose and fat. And so this can cause a lot of oxidative stress.
so then when, as I said, the fat cells start to get really, really big, the mitochondria become less revved up. Now they're actually struggling to make energy. And so this kind of then causes a stress response in the mitochondria. So it's called an integrated stress response.
Georgia (10:03)
Okay.
Siobhan (10:05)
And this causes a lot of things to happen. One is that the mitochondria might try to get renewed. That's called mitophagy So you start to have fragmented mitochondria. So mitochondria get kind of fissioned, they get broken up, and this is supposed to start the process of mitophagy, but then it doesn't actually go through all the way to mitophagy.
kind of gets broken in the process. And so instead you just get these fragmented mitochondria. They're having even more difficulty functioning normally because a really healthy mitochondria network is something where there's a lot of mitochondria joined together and they can kind of all talk to each other and kind of share resources. So yeah, now you're having kind of two problems where you're not making as much ATP, you're having too much oxidative stress, your mitochondria are fragmented and you can't turn them over.
And so then you are literally now not going to be able to use fat as well. So then this is where these fat cells, which normally should be able to have this process of beta oxidation. So beta oxidation is just basically using fat for energy, is not happening. So fat now just sits there. It's not getting used. These fat cells are not going to get, you know, kind of decreased in terms of their volume. And this is actually sort of a fundamental metabolic.
Georgia (11:14)
Mm-hmm.
Siobhan (11:25)
change that happens where yeah, this is this is something you've heard a lot that people who are overweight struggle to lose weight because literally their fat cells don't want to lose weight. They want to hold on to that fat. So it's a real problem.
Georgia (11:26)
Mm-hmm.
Mm-hmm.
So they're kind of becoming metabolically dormant, essentially.
Siobhan (11:43)
Yeah. Yeah.
And then at the same time, you're also having a lot of these other things that happen with your metabolism, like more insulin resistance. So for instance, I just want to point out this is really key that a lot of insulin resistance can be shown to be kind of fundamentally changed by how well your mitochondria are working in your beta cells or for instance your fat cells.
If you're having cells that are no longer having good functional mitochondria, now this insulin release is not happening as well. And then what
further causes issues with insulin release is mitochondrial oxidative stress. The more oxidative stress you are also producing those mitochondria, the less able they're going to be able to get that insulin release. So now you're having diabetes and you know all the things that play into that as well too. So yeah, there's a lot of things that go wrong with obesity and how your mitochondria are affected basically mean you're now not going to lose weight as well.
you're gonna have less ability to to use energy as well, and you're having a ton of inflammation, which can cause a cascade of I would say age acceleration in your body.
Georgia (12:55)
Mm-hmm.
So does this sort of one of the reasons why that whole calories in, calories out sort of way of thinking about obesity just doesn't really work? Or is this actually a part of that calories out problem?
Siobhan (13:14)
I think we're really starting to understand that that calories in is it's it's valid in terms of physics, but when you come down to the biology of like how we metabolize fuel in the body, yeah, it's it's not so simple. So it it really is there was actually a very recent study that that showed when a GLP1 agonist was given to overweight people that were on a very restricted calorie diet.
Georgia (13:29)
Uh-huh.
Siobhan (13:41)
Compared to the controls that were also in the same amount of calories, the same amount of restriction, this GLP one, and it was Retatrutide basically had a higher metabolic, a resting metabolic rate. So you were literally using more calories with the GLP one. So I think that kind of gives you that sense of, yeah, it is basically how much your body wants to rev up energy use in an efficient way.
Georgia (14:04)
Mm-hmm.
Mm-hmm. So for revving up energy use GLP ones, what are they specifically doing to the mitochondria? Do we have any evidence for how they interact with them?
Siobhan (14:11)
Ha ha
Yeah, we're we're starting to see more and more evidence, and and hopefully there'll be more coming through. I think this is only just being touched upon in the last few years, but clearly GLP ones beyond the appetite control are having a lot of effect on the mitochondria or fat cells, our muscle cells, even our beta cells. And this brings them back to a more healthy metabolic level. So so that's huge. And not only that.
when you do have something like a GLP one coming into your body and basically telling your body like, okay, we're going to yeah, start to use glucose more effectively, then all the other things that I just talked about start to go away. So your insulin resistance starts to go away. And this is of course really important. It's been shown again and again that a GLP1 can help increase insulin release. But moreover it can also help once again
mobilize that fat in those adipose cells. So how are they doing that? They're doing through several pathways. One is an AMPK pathway. And this is kind of a well-known longevity pathway that we talked about in our last episode, but I'll just briefly say AMPK is a signal of low energy. And so it's basically telling mitochondria like you need to make more energy and you also need to do need to do a bunch of sort of metabolic changes to kind of get you ready for
stress and stress in this case through MP activation is a good stress. So it's kind of making you more metabolically efficient. And then it's also increasing PGC one alpha, which is this very key mitogenesis marker. So also making sure that you're gonna make new mitochondria. And those new mitochondria, as I said, you know, they can actually do that job that all those fragmented mitochondria could not do.
So all these things are very helpful. And then moreover, just the sort of data coming out is just showing that the mitochondria themselves are now acting a lot more kind of healthy in terms of it can increase the kind of respiration complexes. So all these enzymes are important for making energy. And it can also help with yeah, that kind of inflammation that's occurring. So basically make it so that.
the integrated stress response that's causing all this inflammation in the fat cells and then other cells as well. Now they're gonna be more, I would say, kind of calmed down. And so that allows the mitochondria to work better as well. So it's like a kind of virtuous signal in a way, like a sort of circle of just like we're having healthier mitochondria and then all the sort of things that we're doing to the rest of the body can make the rest of the mitochondria in the body also healthy.
and then the other thing that's I think really interesting that I should mention is that it's been shown for people who are overweight or obese, they have less GLP one signaling just in general. So they have a meal and they don't make as much GLP one as they should. And yeah, this is a problem, but interestingly enough, GLP one agonists can actually help natural GLP one signaling come back as well, too. So that's kind of fascinating.
one other thing that's really interesting about GLP ones that has, yeah, kind of recently been thought of as maybe just a small effect, but maybe it's not such a small effect, is that GLP ones also seem to be turning white adipose tissue into brown adipose tissue. And so we talked a little bit about brown adipose as being this kind of very mitochondrially kind of active cell type. And so this is where the mitochondria
Georgia (17:57)
Mm-mm.
Siobhan (18:09)
Unlike a regular white fat cell is now making a lot of energy just to make warmth, to make heat. And so it's basically just burning away your fat, but not even making ATP or anything else like that. And so there's yeah, a recent study that actually just came out ⁓ showing that people on GLP ones literally have more brown fat after taking them for a while. So that's that's another area that could be helping your metabolism get back to what it could be.
Georgia (18:15)
Mm-hmm.
Yeah.
Mm.
So when we go to brown fat and we start burning energy as heat instead of as ATP, creating ATP, does that mean that we're also creating less oxidative stress and inflammation through that pathway? Okay.
Siobhan (18:51)
Exactly, yeah. So that's that's the other
thing that the nice thing that's happening. So yeah.
what we know for sure is that when they're a Liraglutide that's a GLP one agonist.
Is given to mice, it's not only increasing mitochondrial number and also the mass of mitochondria in, for instance, cardiac muscle, it's also doing somewhat the same thing in other kinds of you know models of diabetes, for instance. So really bringing mitochondria kind of back into a functioning state. And so this is where I would say the main effect of GLP-1s and mitochondria is just literally giving them back.
that kind of functioning of the oxidative phosphorylation, making ATP more efficiently with less oxidative stress, and also bringing back that ability to make more mitochondria.
Georgia (19:41)
So exercise, we know that exercise is important for mitochondria. We kind of went into this in our last episode.
And specifically for these GLP ones, there's some stories that are coming out now about muscle loss when you're on these medications. Could you talk us through maybe some of those mechanisms that are happening there? Is it just a case of when you're eating less calories, you're going to lose a bit of your lean mass, or is there something happening with these medications on the way that you hold on to muscle?
Siobhan (20:09)
Yeah, so this is a big controversial area right now of do GLP1s really cause extreme muscle loss, or is it kind of on par with what you see from someone just on a calorie restriction diet? And so I will just kind of start talking about some of the studies that have shown, for instance, some, you know, pretty substantial muscle loss. For instance, in the Surmount-1 study, this is terzepatide.
There was a 10% reduction in lean mass over 72 weeks, which, you know, doesn't sound so bad, but you know, the other kind of situations of earlier studies have gone to show that up to 25% of the total weight loss ⁓ is lean mass. And so that's a pretty big area in terms of you know how much lean mass you've lost. And there's a lot of discussion too about.
Georgia (20:55)
Mm-hmm.
Siobhan (21:04)
Each time you might go on a GLP one and you lose some lean mass, you then, yeah, might kind of start to gain the weight back and you're gaining the weight back mostly just in fat, but you don't seem to gain back the muscle. And that's I think the real issue right now is not so much like how much lean mass did you lose in the first time being a GLP one, but is it kind of going on and on, you know, each time you go on and off to the point you're losing more and more lean mass and
Georgia (21:18)
Mm-hmm.
Yeah.
Siobhan (21:33)
Yeah, just gaining fat. So that is, I think, still a big controversy of like what what is the real situation. The main thing that people have come out and said is that for instance, some of these lean mass ⁓ statistics may not be as bad because for instance, when you measure lean mass through a DEXA scan, you are also measuring, for instance, liver mass. And in a lot of people who are overweight or obese, they're actually having
A lot of fatty liver. And so as you lose weight, you're losing your fatty liver, and that's counted as lean mass loss. So that's one thing. And then the other thing is, you know, is there something really special about the GLP ones that cause particularly lean mass to go away that is just not even something just related to less calories? Because that's the big story, I think, right now is that we know a lot of people
Don't eat a lot of calories and protein. And when you don't eat a lot of calories and protein, you're gonna lose more muscle. Like that is just how it's going to happen. And I will just give you, for instance, a study that came out recently where they basically surveyed people on GLP1 agonists and said, you know, how much are you eating per day? Fascinatingly enough.
Georgia (22:33)
Yeah.
Siobhan (22:56)
These people reported eating about 700 calories per day, so that's very low. That's definitely not enough calories to probably get the proper nutrients you need. And then in particular, they saw that, yeah, less than 10% of those people were actually eating enough protein, you know, kind of the RDA of protein. So to me, that's already saying in the real world situation, most people are probably not having as much protein as they probably need because they're just eating so little.
Georgia (23:01)
Mm-hmm.
Yeah.
Siobhan (23:24)
So
yeah, that's I think the real danger.
Georgia (23:27)
It doesn't sound like they're eating enough of anything, protein, carbs, or fibre. Seven hundred calories a day is low.
Siobhan (23:33)
Yeah, I mean that that is that is definitely
the the worry. And for sure there are some people out there that are trying to eat enough protein, but I will say even eating enough protein, it might not be enough if you're not exercising as well and you're not doing the resistance training. So another study, fascinatingly, when they started to look at how often people were moving on a GLP one, and this is just recently reported at the Endocrine Society, ⁓
About a month ago, they saw that people reported less activity overall. So for instance, average daily step counts went from 5,000 to approximately 4,400. And so, yeah, that doesn't seem like a lot, but it's it's showing that unlike probably what people are hoping, that you know, there's a lot of discussion about all right, you know, you're gonna take this GLP1, go and exercise.
People are not following that recommendation. They're feeling less like they want to exercise and that's being reflected in these ⁓ in these kinds of studies.
Georgia (24:29)
Mm-hmm.
Yeah. Do you think that that is just a case of if you're eating such a low calorie diet, you do not have the energy to be exercising or is this like a motivation or the GLP one is doing the work for me? Do you have any idea?
Siobhan (24:54)
This is such an interesting area because I think there is a lot going on with motivation with GLP ones, but just to kind of stick with is it because they're just not eating a lot of calories and they're feeling tired? I for sure think that's part of it. That yeah, you you feel like you don't wanna eat and that everything is fine, and then you go throughout the day and you just find you're less and less able to go for that long walk. ⁓
Interestingly enough, there are a subset of people that talk about how when they get onto GLP one and they see the weight going off, they get super excited and then they love going to the gym because it's suddenly easier to go to the gym. I would argue this is a pretty small subset. So I think most people go on GLP1s and mostly they just feel, for instance, in the first few days, a little bit of those symptoms I talked about, like nausea.
Georgia (25:32)
Mm-hmm.
Siobhan (25:47)
A little bit of that feeling kind of, you know, gross or out of it. And this definitely makes you not want to exercise. So if you're nauseous, you're definitely not gonna go to the gym and do like a hard workout. Over time, when they, you know, get more kind of through their week after their injection, they probably feel a little bit more like exercise, but now they're probably just trying to look at, I wasn't doing much for my first few days, you know, in terms of productivity. I probably have to do all the other things in my life.
Georgia (25:56)
Mm-hmm.
Siobhan (26:14)
That I put off. So usually exercise is always one of the last things that people feel like they can make time to do.
Georgia (26:17)
Mm-hmm.
So I was gonna ask like, is this fear of losing muscle overblown? But I feel like it probably isn't. If people aren't eating much and they're not working out, yeah.
Siobhan (26:31)
It's yeah, even
if you would find out, and I'm hoping that we find out over the next few years that there's nothing special about GLP ones really making you lose lean mass or muscle, that's just the fact that you're not eating enough, like that's enough to make it so that you're not going to maintain your muscle as you lose all this weight. So I think that's a real problem and I I don't think anyone's
Really cracked it that well because a lot of them are getting, for instance, the GLP ones off of these telemedicine platforms where there's really no doctor kind of overseeing your progress and not really getting that kind of behavior change of you need to put exercise in your life and you need to do it permanently. And so, for instance, ⁓ as you know, I used to work for Noom, and Noom has this whole behavior change program of you know comparing, ⁓
Georgia (27:17)
Mm-hmm.
Siobhan (27:27)
Just, you know, diet and and sort of exercise alone sort of advice is not going to be enough unless you give people like strong habit-changing instructions, which is what Noom does. When they pair this kind of habit-changing, sort of behavior change weight loss regime they've got with GLP1s, you actually get a lot more, I would say, results in terms of the weight loss, but then also kind of keeping your weight down after you go off.
the GLP one as well too. So and I think this is literally very important if you think about after you go off a GLP one, what's gonna burn the most calories in your body? It's gonna be muscle. So if you still retained a lot of muscle because you did that exercise, because you kept those calories coming in, you're gonna do better overall.
Georgia (28:08)
Yeah.
Yeah. So if you are someone who is taking a GLP one and you just aren't that hungry, but you have just listened to this podcast and you now know that you need to be eating potentially more calories than you think and a a big portion of those calories should be coming from protein. ⁓ is there something that you can do to help either increase your protein level or something that you can take alongside this GLP one to support muscle health?
Siobhan (28:45)
Yeah, the there are obviously a few tricks I would say nutrition-wise that people should be aware of. And so one I would say is people should take a multivitamin. Cause clearly, like that study I just talked about, where they showed that people are taking less calories and less protein, they also showed severe deficiencies in vitamin D and also potassium and calcium. And so for instance, vitamin D is very important for
improving our insulin response and especially improving it after we go off those GLP1s. So keep your vitamin D levels up. And then the other thing is that a lot of I would say very key vitamins for mitochondria function, so the B vitamins, so for instance vitamin B12, ⁓ this is something that even if you feel like you're taking enough through your diet, when you have that decreased gut motility,
Georgia (29:19)
Okay.
Siobhan (29:41)
From the GLP1, it also means that B12 doesn't really get the chance to get absorbed as well. So even if you think you're taking enough, you are probably not taking enough. If you're taking that 100% RDA, it's probably still not getting through you. So if you want to keep your mitochondria running well, and you need to ⁓ with some more B12, then you probably definitely need to take a higher dose through a multivitamin. So that's one thing to think about.
Georgia (29:43)
Mm-hmm.
Siobhan (30:10)
And then the other thing I think is really important for people to understand is that when you go off a GLP1 and yeah, the food noise comes back and all the rest, the thing to realize is that your metabolism that you had before, that kind of dysfunctional mitochondria, also come back quite quickly. And this is because of epigenetic changes.
Georgia (30:29)
⁓
Siobhan (30:31)
And so with people who are overweight or obese, they have methylation profiles that are actually showing that mitochondria function is going to be, I would say, dysfunctional for quite a long time. So these epigenetic changes show that you're going to have less lipolysis, so like less ability to turn fat into energy.
Georgia (30:44)
Mm-hmm.
Siobhan (30:55)
And your oxidophosphorylation genes are also kind of being silenced, and your mitobiogenesis genes are also being silenced. It might take a while to get those back on track. So you to have that long-term methylation changes that help your metabolism rev up again to someone normal. And this is why I think a lot of people, when they lose weight, they suddenly realize, like, you know, I I feel like that I should just now be able to eat.
The same amount calories as all my friends, but in fact they find out that's not the case, that they can eat much fewer calories, but they're still kind of gaining weight. And that is, I think, the most frustrating thing about weight loss. And I think this is because of these epigenetic changes. So, what can you do about these epigenetic changes? I would say the first thing you should probably do is think about your gut and think about your microbiome. So, one thing I would suggest is you try to get back a natural GLP1 release.
Georgia (31:32)
Mm.
Siobhan (31:53)
And so one good way of doing that is getting your gut to make a lot more short chain fatty acids, from for instance, from fiber, and also from certain microbiome bacteria as well too. So I would suggest everyone starts to eat much more fiber to kind of help with short chain fatty acid production and GLP1 production, and also take in certain probiotics. akkermansia muciniphila go a lot of sort of credibility right now, but
There are even just lactobacillus probiotics that have been shown to help increase GLP1 signaling kind of in a long-term way. So I think that's a really important thing for people to focus on.
Georgia (32:35)
So it sounds like it's when you ⁓ go off a GLP1 medication, there's this sort of period of time where you are likely to put some weight back on. And it's not necessarily just because you don't have that appetite suppression and the food noise comes back. There's changes to your mitochondria, there are changes to your gut microbiome. So you've really got to take care of your whole system while you're on the GLP ones as well as coming off of them.
Siobhan (33:04)
Yeah,
I think this is what I'm saying. So you really have to be careful why you're on the GLP ones, that you preserve that lean mass and you you keep exercising and you also start to get your whole body ready for going off by taking in more fiber, getting your body ready to make more natural GLP one.
Georgia (33:23)
Do you know how long most people are on a GLP one for?
Siobhan (33:27)
I mean, I would say at this point, people have been on it for years. And so this is the big question of just, you know, can you stay on these forever? Is that a good idea? And I am very reluctant to think that you should just be on a GLP one forever. I know some people have been talking about them as longevity drugs of just kind of like, they fix your metabolism, they fix everything. I mean, we haven't even talked about how GLP ones are now being kind of shown to help with
Georgia (33:31)
Mm-hmm.
Mm-hmm.
Siobhan (33:54)
overall heart disease and fatty liver and like even addiction. But I also worry about the changes that are happening in your brain with a GLP one that could be long term and might be something that, you know, is a problem for some people.
Georgia (34:09)
Hm. Yeah, did you want to go into that? You've got your neuroscience background and we know that food noise is sort of all tied with dopamine signalling and motivation. So is there something that's happening in the brain, not just in the stomach, these medications?
Siobhan (34:22)
Yeah, yeah. So
clearly everyone notices the food noise goes away and their cravings go away. And it's well understood this is a dopamine-mediated mechanism. So GLP1s are basically causing appetite to go down because, for instance, dopamine that normally gets released into areas like urocaudate.
are is no longer getting and your accumbens, your nucleus accumbents, this is these are sort of reward centers of your brain that also help with motivation. This is this is all lessened. And so we really see that especially when people go in GLP1s and even just other kinds of addictions that they have, not just to food, but for instance alcohol, also go away. So there's a lot of anecdotes and then now there's even some clinical studies showing that people who used to drink
Georgia (34:51)
I'm like, define this please.
Siobhan (35:16)
you know, maybe like three or four alcoholic drinks a night are now feeling like, I'm fine with just one, or maybe no alcohol at all. And this is because, yeah, the dopamine that is motivating them to drink or motivating them to do, you know, whatever kind of addiction behavior they have, ⁓ like overeat, is is now tamped down. And so this is, I think, really, really interesting in terms of how dopamine
Georgia (35:34)
Mm.
Siobhan (35:42)
normally works and I will say that dopamine normally works by you know you usually can just increase it a lot and then people get more motivated for something and want it more but what dopamine does not do and I think this is really important is does not make you feel like happier about it. You just kind of feel a little bit more dulled by things. And so I think what is really weird about GLP1s is that GLP ones because of their kind of
Georgia (36:01)
Mm-hmm.
Siobhan (36:12)
Siobhan (36:12)
tamping down of dopamine, they're yeah, making it so you don't want to eat as much and all the rest, but you're also making it so that motivation in general is less and you're also feeling a little bit kind of like dulled in terms of having that drive to do much at all. So for instance, there was a recent study that showed ⁓ sexual behavior goes down a lot when you're on a GLP one. A lot of people say, no, no, no, I feel like uncomfortable for my body the first time. I I wanna like have, you know,
Georgia (36:35)
⁓
Siobhan (36:42)
more romance and all that. But when they actually start to do the real world kind of understanding of, you know, how much is there going on of, you know, sexual activity, GLP ones definitely tamp that down. So yeah. And then the other thing I think that I've heard a lot about with GLP ones is that the the appreciation of food, like feeling like you're really getting a lot out of food, goes down because you have no more appetite anymore. You don't really
Georgia (37:07)
Hmm, yeah.
Siobhan (37:10)
care about, you're not savoring as much. It just feels a little bit like, yeah, not giving that same sort of emotional sort of power that it had. So and some people miss that. I've I've heard a lot of stories, people saying like, I want to enjoy a meal again in that kind of hedonic way.
Georgia (37:21)
Yeah.
Yeah, I mean food is so important in terms of like community building and spending time with friends and family.
Siobhan (37:33)
it's it's just a bummer when you can't get as much out of it. I think that's really important. And then there's the whole area of like depression, of you know, do GLP ones cause people to have more depression or less depression? And this is where the jury is still out because some studies show that people on GLP ones are having less depression.
And that kind of makes sense in terms of if you can imagine someone who's been overweight for a lot of their life and they've struggled with food and they have this food noise and it's a lot of anxiety, and now the GLP ones have taken that away because they're losing weight, so that probably feels great. But I I also think, especially for people who are more prone to depression, like they should watch out because yeah, the the loss of kind of motivation for anything in their lives.
Georgia (38:08)
Mm-hmm.
Mm-hmm.
Siobhan (38:22)
is definitely a depression symptom. And so it's just kind of understanding maybe you feel good about your body for the first time in your life, but also appreciate if you're still feeling that kind of joy in life. And if you're not, then you could be heading towards depression. And there have been some studies also showing that depression ⁓ rates do go up with GLP ones. So yeah,
Georgia (38:38)
Mm.
is that with people that have depression is the severity increasing or does it mean that anyone can be more prone to developing depression if you're on a GLP one?
Siobhan (38:55)
Yeah, so I don't think this is especially clear. It's probably to to my feeling going to be more of a problem if you are someone who's more prone to depression that you might get a kind of worse effect from GLP ones. So yeah, that's that's sort of what I see so far from the literature, but it it could change. And so yeah, this is this is still out there.
Georgia (38:58)
Yeah.
Siobhan (39:20)
One interesting study that I do want to point out, because this was kind of fascinating, is that one ⁓ group tried to look at how motivation was changed with semaglutide, for instance. So people who had depression were basically given a task that's called the effort expenditure for rewards task. And this is where, in a computer task, you're basically doing these kind of tasks to try to get money. And they showed that.
For depressed people, they were actually doing better, getting that money reward, you know, kind of working harder for it than yeah, people who are just getting the placebo. So that would indicate to you that it's helping with motivation. But I would also say, well, these people are depressed already. Maybe the GLP ones kind of helped, you know, their dopamine look get a little bit sort of more normalized. But I would say,
Georgia (40:14)
Mm-hmm.
Siobhan (40:15)
I would wonder if they would get the same effect for, for instance, people who are not depressed. yeah, so that's I think a big a big issue right now is not really knowing exactly how dopamine will change in a long term either. So I would love if someone started to look at how dopamine is changing and motivation is changing in people who are taking GLP1s long term. Cause there is there is this whole, I would say, syndrome now and ⁓
Georgia (40:22)
Mm.
Yeah.
Yeah.
Siobhan (40:43)
This has been talked about in the New York Times, for instance, which is Ozempic personality. And it's yeah, literally that personality of like the the just this feeling of like I am not caring as much about just basic things in my life.
Georgia (40:56)
Mm.
It makes ⁓ these GLP one medications quite different to things like bariatric surgery then because I know that if you are a candidate for bariatric surgery, there's this a process that you have to go through where you are assigned a counsellor because if you if your stomach is shrunk and you physically can't eat as much, if you have a vice for food for ⁓ seeking dopamine and you can't do that anymore, that can kind of shift into other things. So you're potentially at more of a risk of developing
Like alcoholism, for example. But these GLP-1 medications, it's not like that at all. It's like dulling the entire system down.
Siobhan (41:35)
Mm-hmm. Yeah.
And and this is where they've even done studies showing that literally even the taste of food decreases with GLP ones. So literally even like the way you're sensing taste is just a little bit blunted. So yeah, which we you would not get with bariatric surgery.
Georgia (41:49)
Yeah.
Yeah, yeah. So if you're on a GLP one, how can you help to support this dopamine system? Is there anything that you can do or take to make sure that you still have some joy or motivation more so?
Siobhan (42:08)
Ha ha.
Yeah,
I mean I think that the you would probably have to do the things that we've already discussed, which, you know, can already be problematic. Like exercise for sure. If I had to choose the main way that you can deal with depression, deal with anxiety, I would say exercise the best way because exercise does release endorphins, these kind of, you know
basically pleasure sensations and also dopamine and also increases neuronal growth in the brain and that you all can make it so that you are able to stave off depression and have a better mood. So for sure that's that's still an option. Eating enough protein, as we said before, is is also important just to make sure that once again you can keep you know your neural health up and and make sure that you're producing more dopamine. ⁓ and then meaningful social interactions. So
Georgia (43:03)
Mm-hmm.
Siobhan (43:03)
Yeah, when
you're around people you love and having a good time, you'll increase dopamine levels. So that's that's the other thing. But I would say a lot of other things you might want to like think you could do with dopamine, for instance like dopaminergic drugs or anything else like that, I would not go there because I feel like, you know, now you're getting into a whole area that is un not understood that well.
Georgia (43:22)
Okay.
can you let me know how eating protein influences dopamine responses?
Siobhan (43:31)
Well, one way it could help with dopamine is just the fact that tyrosine, this amino acid that you get with, you know, good protein I should say, so mostly usually animal protein, ⁓ this is basically turned into dopamine. So if you don't have adequate tyrosine 'cause you're eating so little protein, you're not gonna make enough dopamine. So that's that's one thing.
Georgia (43:47)
Mm-hmm.
Okay, so it's sort of all interlinked then. Yeah, okay. So protein isn't not just for muscle, it's also for brain health and mood. Mm-hmm.
Siobhan (43:57)
Yeah, it is all interlinked as usual. Yeah, and mm-hmm.
Yeah, it's also for making those neurotransmitters, so you
gotta have it.
Georgia (44:07)
So I feel like we know a little bit more about how mitochondria are involved with our metabolism and how GLP1s are affecting that. The importance of proteins specifically for maintaining that lean muscle, for cognition and mental health as well. What are some things that we can do as a lifestyle modification or potentially some supplements that we can take to support our brain and our body while we're on a GLP1?
Siobhan (44:36)
Yeah, so we have to start off with exercise and like overall good diet. It's just it's it's a needing to just make that super clear. So exercise, even small chunks of exercise. When I was at Noom, it was always that problem of like how to get people to want to do exercise that don't normally like to do it. And it's kinda like do it in small chunks, you know, take some extra stairs, like get up and start to walk around when you're taking a call, something even as basic as that.
Georgia (44:43)
Mm-hmm.
Yeah.
Siobhan (45:05)
And then resistance training, you know, a lot of people want to go to the gym. So I tell people get a band, one of these like resistance bands, and literally while you're watching TV, use the resistance band for five minutes. So that kind of stuff. The other thing with the diet is that for sure, you've heard stay away from ultra-processed foods, but I also just want to bring it even to more of a sort of situation of stay away from inflammatory foods, because
Georgia (45:16)
Mm-hmm.
Siobhan (45:32)
Inflammation, especially while you're on GLP 1's is not your friend. Inflammation's going to kind of keep that kind of metabolic dysfunction going that I just talked about. So staying away from saturated fats, from too much glucose, which isn't usually a problem for people, but yeah, it's still just really worth saying you still need to eat a ton of those anti inflammatory foods like the vegetables, like the fiber. Yeah, and I will say.
People emphasize protein a lot. I would like to emphasize fiber. I think people really need to have a lot more fiber in their lives, and that's going to bring back more of a normal GLP1 response, which is really what you want in the long run, but it's also going to make it so that you have a better metabolism overall. So, yeah, those are the main things. But then I also just want to talk about a few kind of supplements that people could try just to kind of nudge things
Georgia (46:05)
Mm-hmm.
Siobhan (46:28)
one is creatine, that's kind of a darling of the supplement world right now, but creatine is very good to help build that lean muscle. So, yes, this is obviously a really useful supplement, and the fact that it's promoting you know ATP buffering, which is kind of recycling ATP, especially in your muscle.
So then it can kind of influence those salite cells to then make more muscle for you. So that's a huge thing. Just don't forget to do your resistance training while you do the creatine. That's the main, the main thing to remember. It's not gonna work by itself. You need to do the resistance training to build that muscle. ⁓ another one is taking NAD precursors. So NAD, I think everyone kind of remembers, is this really important kind of
Bioenergetic factor that allows your mitochondria to make ATP. And so NAD declines with age and it definitely declines with obesity and diseases diseases related to obesity. So bringing your NAD levels back up again can for sure be very helpful for your mitochondrial metabolism. So something like nicotine riboside or nicotinamide mononucleotide or even just niacin can be very helpful.
Georgia (47:47)
So
Siobhan (47:47)
And then I will mention MitoQ because MitoQ is also another thing that I would say is very good for promoting better effects from exercise. So Mito Q in several clinical studies has been shown to improve muscle power and then then also helps with muscle mitobiogenesis, so increasing mitochondria in muscles, which then can go on to help with you know building more muscles
And then also, interestingly enough, one animal study did show that ⁓ in an overweight kind of high-fat diet mouse model, that MitoQ could protect mitochondria and also even increase GLP1 release, so that kind of natural GLP1 release what that you really want. ⁓ so yeah, that hasn't been shown yet in human studies, but I I'd love if someday we could see a human study that goes into that. And yeah, I would say the main thing to remember is that.
Mitochondria oxidative stress, which is also very, very high when you're overweight, especially when you go off the GLP one. If you're still overweight, you're still gonna have more oxidative stress than someone who's thin. So you wanna protect your mitochondria by decreasing that oxidative stress, which can lead to the inflammation and insulin resistance.
Georgia (49:05)
Mm-hmm.
MitoQ is also really important for cardiovascular health. Does that include cardiometabolic health? Is there a mechanism there for MitoQ?
Siobhan (49:14)
Th there there
is. And so yeah, I I would definitely recommend MITOQ for just overall cardiometabolic health, so improving vascular function, which can also go down with people with obesity. But you know, there was a really cool study that also looked at whether MitoQ can help with insulin sensitivity and humans. And so yeah, that was also shown people who are
Overweight, who are pre-diabetic when they were given a large dose of MitoQ could maintain insulin sensitivity even when given a large bolus of fat. So, yeah, once again, I think these kinds of things that you know keeping your mitochondria able to respond well to you know high energy demands and then also what it's called lipotoxicity when you have too much lipids in your system. Like this is all very beneficial for.
Georgia (49:52)
Mm-hmm.
Siobhan (50:11)
the times that you might overeat in the future, because obviously that's that's still always a thing. I I think this is where even people who are taking GLP1s, I have heard stories of, you know, overeating, especially when you get down to the day before your next injection, that you can start to overeat again, the food noise comes back.
Georgia (50:17)
Mm-hmm.
⁓ so it sort of wanes off the further you get from your first injection. Okay. So that's something that you've gotta consider.
Siobhan (50:35)
Mm-hmm. yeah.
so making sure that you're trying to take in the same amount of calories every day is really key. You don't want to starve yourself in the first part of the week after your injection and then start to overeat as you get to the end of the week. That is obviously bad news for your metabolism.
Georgia (50:57)
So how much protein is enough to be taking when you're on a GLP one?
Siobhan (51:02)
Yeah, well for sure, reviews have shown that protein intake that is less than one gram per kilogram per day is associated with more muscle decline, so risk of losing muscle. So yeah, you should try to keep your protein intake to at least 1.3 grams per kilogram per day, just to make sure that you can keep increasing your muscle with resistance training and just maintaining that muscle.
Georgia (51:15)
Mm-hmm.
Siobhan (51:30)
And so the thing that I would also just point out too is that people usually want to do protein powder is the easiest way to get extra protein in that sort of situation, but you have to think about usually what else is added to protein powders, which is a lot of artificial sweeteners and fillers. So those I think are ultra-processed foods and cause that kind of inflammation as well. So really consider trying to get just pure protein, you know, go crazy with hard-boiled eggs or you know.
Georgia (51:50)
Mm.
Siobhan (51:59)
beans or things like that. That's the better way of doing it.
Georgia (52:02)
Mm. So taking it from whole foods rather than supplements. Yeah. With the eating like one point two to one point six grams per kilogram per day, is that your current body weight or is that the goal body weight that you're going off of? Okay.
Siobhan (52:19)
Yeah, I would say this is your current body weight. So you still
have to support your body just the way it is right now. And yeah, this is where one one one point two to one point six grams per kilogram, that is kind of the sweet spot of where you should be.
Georgia (52:26)
Mm-hmm.
Mm. But for some people that is quite a lot of protein. Yeah.
Siobhan (52:38)
It is a lot of protein. It it's really
daunting at first. And so yeah, you just have to have those those quick, easy ways of getting protein into, like I mentioned, you know, having hard boiled eggs or the cheese or something that you can have as a quick stack.
Georgia (52:53)
Mm-hmm. And I guess bone health is also really important for one, making sure that we preserve that muscle mass, but is there anything that we can take to support that as well?
Siobhan (53:03)
Yeah, so this is I think where I hate to say this exercise is really helpful for the the the bones as well too. So kind of keeping them also, you know, making themselves, regenerating themselves during the GLP one, but you know, also taking just those required nutrients that we're probably very deficient in, like calcium and vitamin D, ⁓ all those kinds of things also need to be done as well too.
Georgia (53:08)
Mm.
So exercise really important, especially resistance training. And I know that some gym memberships will offer things like a DEXA scan so that you can have a look at your body composition. Is that something that is worth doing?
Siobhan (53:44)
for sure. Yeah, I love the idea of people trying to follow how they're changing their body composition, especially that that bone part of it, just to kind of make sure that you're not losing extra sort of bone, but then you're also kind of maintaining your lean mass as well, too. So I would even tell people, anyone starting on a GLP one, even if you don't have a DEXA nearby, maybe go seek one out just to kind of have even a baseline of how you are when you start that GLP one so you know.
Georgia (53:52)
Hm.
Mm-hmm.
Siobhan (54:12)
at least what kind of muscle mass and what kind of bone mass you should be maintaining.
yeah, so Georgia, I think what we've really gone over today is that GLP1s might have a lot of potential for mitochondrial health. And I'm very excited to see how that goes in the future. And we've already had these sneak peaks with these animal studies showing that GLP1s can improve mitochondrial oxidative phosphorylation.
Mitochondrial biogenesis, mitophagy, which are all decreased in overweight or obese people. So that's really exciting. And then the other thing I would say that's really great about GLP1s is that they are something that can help feel like, you know, I'm going to lose that weight. But while you're losing that weight, you still need to think about your muscles because, for instance, the mitochondria in your muscles.
really they can start to degrade and not do well if you're not feeding them well enough during the GLP one kind of dosing. So kind of making sure that you're getting all that adequate diet, all that exercise to maintain muscle and your mitochondria at the same time, that is absolutely key.
Georgia (55:23)
Mm-hmm. And protein is a huge part of it for muscle health. And also, yeah.
Siobhan (55:26)
It is a huge part. But other things can also really help, like
that fiber and yeah, really making sure that you're getting all those vitamins and nutrients that you need to have for your mitochondria.
Georgia (55:39)
Absolutely. Thank you so much, Siobhan for joining me. It was a great conversation and I learnt a lot about GLP-1s
Siobhan (55:46)
Awesome. Until next time.
Georgia (55:48)
See you.
