March 3, 2022

"Nutrient Timing and Metabolic Regulation" with Professor James Betts

Episode 170 of the Institute of Performance Nutrition's "We Do Science" podcast! In this episode, I (Laurent Bannock) discuss "Nutrient Timing and Metabolic Regulation" with Professor James Betts PhD (University of Bath, UK).

Discussion Topics Include:

  • Defining the concept of "Nutrient Timing"
  • The mammalian circadian timing system: Metabolic Clocks
  • Rhythms in macronutrient metabolism,  energy expenditure, and appetite regulation
  • Nutrient Timing: Extended overnight fasting, Intermittent fasting, Nocturnal interventions etc

Podcast Episode Transcript: Download PDF Copy

Key Paper(s) Discussed / Referred to:

Related Podcast Episodes:

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[00:00:00] LB: Okay. So welcome back to the Institute of Performance Nutrition We Do Science podcast, the IOPN podcast. I've been doing this podcast for quite a while now. It's been quite a few years. And I've had the odd year where I've not done much many because I've been working in team sports, tournament sports, that sort of thing. So I've dipped in and out of my efforts here. But right now, I'm really going back into my podcasting, which I love. And the main reason why I love it actually is entirely selfish. It's because I get to talk to people who really have an incredible depth of knowledge in certain areas that I wouldn't necessarily be able to access if I wasn't having this kind of podcast conversation, and/or I just wouldn't have the time to go visit them all or whatever. So this is a unique situation. And today, we're going to get into a topic with a guest that we've had on many times before. I say had on many times, Professor James Betts. James, how are you, mate?


[00:00:58] JB: Very well, thank you. Lovely to see you again.


[00:01:00] LB: And you mate, yeah, yeah. I mean, everyone's listening to the audio. But for some reason, I just don't do the video of this. It's probably best actually. It's probably be best. But I said, welcome back. You have done a couple of podcasts with us over the years, and you've lectured for us quite a few times on our various IOPN events. And before, I guess, I go into the specific topic that I was going to get into today. I think, actually, the better way around to doing this is if you introduce yourself, James. Not everyone would have listened to all of my podcasts. They may or may not know about you. But it’d be great to tell us where you're at right now and what you're up to.


[00:01:38] JB: Thanks. Well, yeah, I'm down at the University of Bath. I've been working here. This is my 17th year down here at the University of Bath. I'm the codirector of our Center for Nutrition, Exercise and Metabolism, which is really the headline name for putting together the various researchers we have down here working in this area. So we've, I think, I hope anyway, built up a kind of hub of people working towards a common goal here. 


The kind of work that I do and that the center does is really looking at randomized control trials in human beings is the broad area. My personal interests around nutrient timing, as that pertains to health and also then with physical performance being a part of that. And with that performance link, too, I'm also Editor in Chief of the International Journal of Sports Nutrition and Exercise Metabolism. So managed to keep my toe more than just a little bit in the water with the current thinking in sports nutrition.


[00:02:40] LB: Yeah. Well, I mean, it's very generous of you to spend this time today talking to me, because you're obviously a busy guy. And you mentioned just there one of your interests, which was in nutrient timing, as it relates to health, as it relates to physical performance. And this is a topic that we've covered a lot on this podcast. And also, in our program, we've had loads of lectures. And it's sort of an important aspect of that is to go beyond the word nutrient timing to provide it with a little bit of context, of course, because nutrient timing has been approached by various authors in various journals from a different perspective with a different context focused. And as a result, there are differing views as to the relevance and value of nutrient timing. On the one hand, we might look at it from the perspective of training adaptations, and body composition, for example, in those looking to have a higher quality of body composition as it relates to either aesthetic purposes or strength and power. Obviously, muscle being a focus there. And some others would be simply just a number on scales, weight. And then of course, there is the whole sort of metabolic health thing. 


And yes, they can all combine. But oftentimes, they're approached very differently with different views as to how important nutrient timing may or not be. For example, a common view of the relevance of nutrient timing, simply for body composition, if we keep it as simple as that, is why it's just not as important as overall energy balance, for example. But it isn't that simple in reality, which is why I've done a number of podcasts already on that from those different perspectives and why I wanted to come back to this topic today, because I've read a symposium review that you and your PhD student, Harry Smith, came out on nutrient timing and metabolic regulation. And I find it fascinating for a number of reasons, which we'll delve into today, just this whole complexity of the metabolic machinery. And it really is mind-boggling stuff for those that really want to geek out on this stuff and go beyond the very basic but very important components that we do need to pay attention to in sort of general nutrition concepts. This idea of circadian rhythms and the various aspects that goes on inside of that metabolic machinery is so, so much more complex than that simplistic view that I just described. 


But before we delve into this topic, which I guess we’ll have various rabbit holes that we can go to just on the general idea of nutrient timing for health and performance and so on. What has led you down this path? And it isn't the first. I mean, we've had similar conversations, you and your colleagues, such as Javier Gonzales, Dylan Thompson. I'm going back years now. There's certainly a stronghold of research and focus at Bath with you and your team there. But what has kept you down this path? And what keeps you motivated and excited about this topic? 


[00:05:45] JB: Yeah. So I think one thing in my general approach is I like to think about what fundamental questions we've missed along the way. I always love that if I'm reading about something and realize we've built up to this complex, often overwhelming body of literature. But when you start going back and questioning assumptions, you think, “Oh, hey, we kind of missed some fundamental steps there. Let's go back and fill in the gaps before we answer the next question.” 


So I suppose I can see there's a few areas of my research at the moment, even aside from nutrient timing, where I hope, anyway, I'm going back and looking at those fundamentals. And certainly, timing was one of those key areas that there is just a vast literature on how much of what we should eat. Should we have high carb or low carb, high sugar, low sugar? Those are all questions about how much you eat and the type of thing that you're eating. 


And I feel like a broken record here, because I'm always saying this, but I think the third component of amount and type is timing when you're eating it. And in some ways, that's a more fundamental question, because that isn't just about how much you're eating. It's about whether you do it at all, the absence of nutrition, versus the presence. 


So like I say, in many ways, the most fundamental question you can ask about nutrition is whether you're getting any? Yeah, this whole area of fasting, and meal timing, nutrient timing, seems to me to be one of the really fundamental areas where there's a real lack of information in relative terms. And so yeah, it's going to keep us busy, at least for the rest of my career, because there's so many questions to answer. And so many of the studies we do, as most science does, raises more questions than it answers. But I think that's a good thing.


[00:07:32] LB: Yeah, absolutely. Well, look, I mean, it's not like this isn't an interesting, if not hotly debated topic. Like I said, it does depend, as always. It depends. And sadly, a lot of people don't do things that I try more and more lately, at least I've tried to get into in this conversation, is define what people mean by nutrient timing and define in what context they're even talking about. And that phrase, it depends, or context. What are those contexts? And in what scenarios is this stuff likely to be more or less relevant, particularly when you start to think, nowadays, modern human beings, but particularly modern athletes, of course, travel a lot. So in that situation, you've got demands on time. There're significant issues with practicality of preparing food, cooking food, accessing food. Even being able to afford food. Not to mention other issues that could be sort of philosophical, religious, or just plain fuzziness, or whatever. And we then combine that with the requirements to perhaps eat something proximal to a training session or a competition. And/or actually, depending on the context, you’re an elite athlete, or you're definitely nowhere near an elite athlete, it may not be remotely relevant in your particular situation. And much of this stuff tends not to get discussed. It's very black and white, sort of polarized debates. You know, well, it's not important to eat breakfast, which is something that Javier came on at one point to talk about, which you guys have done a lot of research on, which is why I wanted to talk more about this rather than look at it from what has become a more, I guess, well-known perspective of total type and then timing. What do you mean by nutrient timing, James? What does that specifically mean? And then I think we can unpack it.


[00:09:30] JB: Yeah, I'm glad you asked that. Because, again, being a broken record, I start just about every talk I do by let's define terms. There're so many areas of nutrition science in particular, where there's a huge argument and debate. And actually, you realize both people are saying the same thing, but they've just defined the terms differently. 


So yeah, for me, we call it nutrient timing in this review. And one of the journal reviewers helpfully pointed out, we hadn't used the word crononutrition until the end. And that's a term I think we happily added, because that does really what most people mean by nutrient timing brings in crononutrition, the when of eating. And the difficulty here is that we kind of split it in this review in two sections of talking about absolute timing, which is about the kind of time of day and some of the more classical circadian research about when you eat relative to the time that we can all understand looking at our watches. 


But also, the relative timing aspect. Meaning when you are choosing to eat or not eat relative to, and then the list is almost endless. But common things would be relative to the light levels, depending on where you're on the planet, and the time of day. Whether you slept recently, relative to your recent meals. Relative to when you would normally do those things is a really important one. And then lastly, but not least, is relative to exercise, which is where we suddenly find that this area has particular importance for individuals who are physically active, because that's a critical decision then, is do you eat before, during or after your training sessions? And that works both ways. Because if we know that there are certain health and performance effects of eating at a certain time of day, could the exercise facilitate those effects? But then could eating in a certain time to exercise facilitate those? 


I mean, for example, we know that after an intense prolonged exercise, you want to eat more quickly after exercise, rather than leave it a few hours, because you will more rapidly store glycogen. But as I say, there's the other consideration of, well, what if that means now moving your evening meal forward a bit? Is that a good thing to do?


[00:11:44] LB: Yeah, absolutely. And I mean, well, I can’t wait. There're so many angles here that I want to get into. But I'm going to hold back on that, because you used a term, circadian timing, which is sort of at the heart of this stuff that I think for many, I mean, they'll probably have heard of the word circadian rhythm or possibly circadian timing. And I would propose much fewer people would have heard about crononutrition and so on, although we're certainly going to talk about that briefly. And I've got a whole podcast as well we're going to do on that topic. But what is so relevant, anyway, about the mammalian circadian timing system anyway, particularly from a nutrition sort of metabolism perspective? Why is that even an issue? 


[00:12:29] JB: I think you can gauge its importance in one way at least by the fact that every organism has this. And then, as you said, particularly mammals have these rhythms. And when you're looking in just about any organ, or tissue, or cell type in the body, we find the expression of this machinery that is responsible for tick-tocking and knowing what time of day it is. And it doesn't really – It's just intuitive, really, to think what an advantage that would be in evolutionary terms for your body not just to have to react to, “Oh, it's dark. It's time to go to sleep.” Or, “It's morning. I better be ready to go and procure some food.” To have some kind of anticipation whereby your physiology can determine, “Oh, okay. So every day at eight, we have to go out and procure the food for the day.” So your entire physiological system can anticipate that and be ready for the event at the time. 


So intuitively, it makes sense that we should have these rhythms. And the fact that they're just so abundant in the body and in nature, really, I think, attests how important and helpful they can be. And then it's just the natural step on from that to say, “Well, is there anything we can do either to helping train a rhythm that's going to be useful to us? Or at least to recognize what the rhythm is due to other things like your sleep pattern and your exercise pattern, so that you eat at the appropriate times for that.


[00:14:01] LB: This is going to be very interesting to a lot of people for various reasons. And I guess, there's lots of words we're now using. Over the years, I can think of many conversations where we've talked about regulatory systems. And I guess one thing that springs to my mind then is, is where does this fit in all of those regulatory systems? Is there sort of a master and a slave scenario here? What role does it play? Or maybe it's not even possible to answer that question, because we don't even know enough yet. But clearly, you're aware of a role it plays somewhere in that orchestra of events in the body. How significant actually is this?


[00:14:38] JB: Yeah, so the master and the slave angle is an interesting one, because you get kind of – It's a circuit, a feedback circuit. So, essentially, as I said that, your daily behaviors can drive and entrain your rhythms to work efficiently for the next day, but are also then subject to those rhythms and the responses we get. So I think if people are trying to visualize these, a kind of simple way to frame it would be that the classical circadian studies that would feed people constantly are essentially taking away the things that would usually elicit responses. 


So if you take away people's usual exposure to like their usual sleep pattern, their usual meal pattern, some of the metabolic responses that we see over a 24-hour period would persist even in the absence of the stimulus. So there we're really seeing that circadian effect that the body has this inbuilt clock that's going to go on tick-tocking every few hours even if there's no other stimulus. 


But then on top of that, you can layer on these diurnal and nocturnal influences, where if you go to sleep, other things will happen when you sleep. So for example, even if in the middle of the day you shut your eyes and go to sleep, things like growth hormone might start to elevate. So yeah, I guess the circadian system is master and slave. It can be set by our behaviors, but also determine our behaviors and responses to them.


[00:16:08] LB: I mean, I haven't pre-thought this, but what's coming up in my head is very much this idea of it's like a manual watch. I mean, we're not recording the video. But I'm thinking like in sort of the watch I’ve got here, you've got like a mechanism you can see on the side. You start tightening out. But also, there's this concept of a power reserve in your watch. And if you don't stay on top of it, that reserve starts to drain away to a point that it won't become functional. But also, over a long period of time, that mechanism becomes less efficient over time as a result because of that lack of stimulus, which is just moving your hand around, or whichever, which could, I guess, link to physical exercise and activity with some degree of regularity. Because if you don't do it often enough, your watch is sort of draining its resources quicker than it accumulates. Then I'm sure that analogy is probably not holistically remotely going to cover this aspect. 


But in my head, there's a sort of – It sort of makes sense, because you talk about clocks and various things in the paper. And this is a very difficult concept to grasp. I mean, you're in the gym, you're doing whatever, and you think about lifting something, and there's muscles. Or you might delve into energy metabolism and so on. But the very idea that there's these rhythms and as these sorts of controlling regulating systems, and there's clocks in different parts of the body, and so on, maybe you can help us piece that picture together, because it's pretty mind-blowing.


[00:17:35] JB: Yeah. There're so many papers that paint that picture. They talk about clocks in different parts of the body. And certainly, the imagery you see on journal covers, they love to draw these tiny little pocket watches within each cell. So it is kind of interest – And it's not far off to talk about it like that, because a clock is just a set of machinery that keeps to time. Interestingly, there was a little riddle that one of my boys saw somewhere, which was what type of clock has the most moving parts? And the answer was a sand timer. But I spoke to John Johnson at Surrey and he said, “No, it's the mammalian timing system,” because when you think of the number of molecules involved. And then of course, the other part of the question was which type of clock has the fewest number of moving parts? But maybe we'll leave that one in the chat, if anyone listening can come up with the clock with the fewest number of parts. 


But yeah, there are literally these clocks, centrally, and in various tissues, that gives you this buffer where you can get the two-way relationship, whether peripheral tissues. I mean, obviously, the eye can give photic input. But all sorts of peripheral signals are going to be signaling to the center what the environment is doing. And then that can be layered on and perhaps change things to anticipate differently, which is why somebody who works night shifts, for example, wouldn't display the same rhythm as somebody who didn't usually do that. 


A more kind of interesting philosophical question I've been thinking about recently, though, is how, if we're still keeping our exercise physiology hat on, is it in many ways makes sense to talk about circadian rhythms and say, “Well, if your body expects this at the same time every day, then do it at the same time, and you will be entrained. Eat during daylight at the same times every day. And that will do for your body what it expects. 


But then if we go to the other – Put our other hat on of being the exercise physiologist, then that's not at all what we do with training, is it? We love to tell athletes, “Shock your body. Stress your body. Progressive overload. Train harder. Train differently.” So I do wonder, whether for athletes, there might even be a case of saying, “Well, do you want to get your body used to doing the same thing all the time? Or maybe straining the system to adjust your rhythm might mean that – Let's imagine, if you're like clockwork and do the same thing every time every day for four years building up to the Olympics, and then you go across a few time zones to the Olympics, this is the first time you've ever had to do things out of rhythm. So I wonder if there is – This is pure speculation on my part. But there could be a case to say, in training your circadian rhythms differently at different times might be a smart thing to do. 


[00:20:26] LB: Yeah, it’s very interesting. I can't wait to discover what you guys and your research colleagues around the world discover as the years goes by. But you've just reminded me of – Well, I mean, I've listened to many fascinating lectures and had many interesting conversations over the years. But one of the ones that really blew my mind was with Dylan Thompson, all those years ago, when he came to talk to us about a number of different topics where I personally was introduced to compensatory mechanisms as a consequence of certain things. And the impact that has on various feedback mechanisms, and so on, which, of course, makes it quite clear that if we look at everything from a very static black and white sort of perspective, it doesn't allow for those things that can happen outside of that very narrow focus that we have either in research, or in a conversation, or a perspective, or, of course, in an intended strategy to deal with something when we haven't thought about the bigger picture. Is there an aspect of that in this, too, where these feedback mechanisms are engaged possibly when we're not on time, so to speak, with these situations? 


[00:21:38] JB: Yeah, I really think so. And as you mentioned, Dylan has many wonderful papers on this. But the terms that I've heard him use frequently are kind of substitution and erosion. And how, if you choose to exercise at certain times of day, might have more or less benefit, not necessarily because of the time of day, but because of what they're replacing. 


So for example, if I go to the gym at the time, I'd usually be walking home. Yes, it's beneficial to go to the gym, but it replaced walking home. If I go to the gym at the time when I usually be sat at my desk, then it's a win-win, because it replaces sedentary behavior. So we definitely do see that. And I think for my part, that's why we started doing the breakfast research here, because I figured, if there's any carryover effect of eating or not eating on behaviors, like snacking, and physical activity, well, do it at the start of the day. And then you've got the whole day of activity to accumulate it. Whereas equally, there's other interventions we've looked at where we said, “Well, why not do those in the evening, because nighttime might be a natural time when you're really not going to compensate for any of the more behavioral responses?” 


So some of our current research and things we're looking to do in the future are about having either a supplement or a meal right before bed or even waking up at night to consume things for the exact opposite reason that if there is any potentially negative effect on behavior, it doesn't matter, because you're asleep. You're not going to eat differently or be more or less active, because we're taking advantage of the sleep period.


[00:23:15] LB: Yeah, no, it's fascinating. And again, for any particular reason I'm saying this. It just keeps sparking off memories lately of conversations I've had, for example, where I had John Hawley on. This is, again, a few years ago. And he was talking very much about the importance of an integrative view of biology, or physiology, or biochemistry, or whatever. From his perspective, it’s sort of a disappointment or dismay on how so much research does not always take that into account, particularly as it relates to taking those findings and then applying them into practice, which is obviously sort of almost going the opposite way. Clearly, there's an element here where these rhythms will interact with signaling pathways and processes, and obviously, nutrient regulation, something we're particularly interested in, of course, in performance nutrition, which I guess brings us to this topic of how does this stuff affect the fundamental processes of nutrient metabolism? And what is the relevant there? 


[00:24:21] JB: Yeah, okay. So, well, to pick up on what you mentioned about John Hawley’s work, the paper that he and Louise Burke published in Science Journal really, I think, captured that whole sentiment, as you say, of being integrative, and not being binary. There was so much debate going on about should you exercise in a fasted state or a fed state? Well, of course, they're just making the point where you don't have to answer that question the same way every single day. Maybe there's some days athletes want to be fed and some days they don't. 


And on the integrative point, yeah, we can show biochemically in terms of the molecular machinery that exercise in the fasted state might elicit a greater stimulus to adapt. But then it's only when you also step back and look at the whole body physiology. You realize, “Oh, hang on. The athletes now are not training as hard. Because those high-quality sessions, they haven't got the drive to exercise.” So yeah, the integrative approach, both in terms of mechanisms to whole body, but also in theory and practice, seem really necessary. 


And I think as it relates to metabolism then, we can layer these things on the same way. So we know that when individuals wake up, whether they’d be athletes or not, we get this thing called the dawn phenomenon, where you would have – Essentially, the simplest way to remember it is that just that your glucose tends to be a bit higher in the morning, and then your fatty acids in the system are going to accumulate over the day. Whereas in the morning, you actually might be better primed to take up glucose. So we tend to eat a carbohydrate-rich breakfast. And you might be better able to tolerate that or to control your blood sugars in the morning. 


So we know that the response to the same meal can differ across the day. And I think an athlete could make use of that to know, even on a rest day, that what they eat is going to do different things to them, depending on the timing. But especially on exercise days, whether that comes before or after exercise, which links to all of Javier Gonzalez work on breakfast timing, before or after exercise. Even if you're actually going to have breakfast, sometimes it might be best to wait till after your workout.


[00:26:40] LB: Yeah. I mean, that brings me to that whole area of nutrient priming, which is fascinating. We were introduced to that at the IOPN on one of our lecture weekends years ago by Lee Hamilton gave us is mind-blowing, overview of nutrient priming. And that was back then. It's obviously come a long way, particularly when you think about nutrient priming in the context of nutrient timing. Then we start really bouncing this one off. And then now I'm going, “Yeah. But hang on. We've got to remember, is this the same for everyone? Or are we talking about – Is there –” Again, you and Javier did a paper about what's the relevance of genetics as it relates to some people wanting to do genetic testing? Is there even a point to that? Maybe we've got more in common than we don't. How much of this is trainable? I mean, boy, this gets quite interesting. Because obviously, there's a limit to what you can put into a paper and you have to – You’ve got a average man of an average height and weight sort of thing. Is there a certain way that you're approaching this topic where you have to – For the sake of keeping it simple? What are your thoughts on that on the sheer, I guess, variability that exists on this topic?


[00:27:54] JB: Right. And I think it's almost impossible to get a handle on that, certainly at the moment. And the reason for that is if we ever want to try and understand individual differences. It takes really quite a challenging experiment to truly understand if there are individual differences. Something called a replicated crossover design, where you essentially do an RCT, which is challenging enough, and then just do it again, with the same people to see if the people you're calling responders are really responders. 


So what we end up with most of the time is just lumping people in categories. So there'll be studies looking at an old group versus a young group, an obese group versus a lean group, men versus women. And if we've got these, often binary, but certainly clear categories, you combine them. And if you find that say, people with more body fat, so an obese group, if they happen to have higher leptin and lower adiponectin, and then you might be able to say, “Well, that seems to be a trait that's consistent, and therefore we would conclude that obesity is correlated with that.” 


Now, why can't we do that meal timing? And it's because it doesn't fit into neat categories? When we did our breakfast research, so many people were saying, “Are these people breakfast consumers or not?” And I think, “Well, do we all get tattooed at birth to say if we're a breakfast consumer?” That it's not the same as male versus female, or obese versus lean. We don't have two binary categories of breakfast consumer and not. Sometimes you are. Sometimes you aren't. And I'm not even too convinced that the people who are hard and fast breakfast consumers and skippers are really that different in their response to some of these things. So it is difficult to do an individualized approach to nutrient timing, for sure. I mean, I don't know how we're going to get closer to that other than comparing groups, because it's such a complex area to work out who's doing what really.


[00:29:52] LB: Mind boggles, James, but you'll find a way, I'm sure, particularly with the advances in technology. If we were having this conversation even five years ago, you may not imagine some of the things that you could do now perhaps. I guess there's always that to look forward to. But you made me think of – Well, you use the words responder and not responder, of course. And that's a can of worms, isn't it? Because some people, maybe, I guess, outliers, and of course, they wouldn't be a responder to that given protocol, because it just isn't something that would fit for them. But I mean, it gets pretty tricky, doesn't it? 


[00:30:24] JB: I would say in my role as an editor, nine times out of 10, that you see people talk about responders and non-responders. There is not good evidence of responders and non-responders there. It's speculation about whether they exist. I mean, on a more positive note, while I have more of a downer on the whole personalized nutrition, because I think we're further away from those things. The other thing you mentioned about nutrient priming, though, that, I'm really excited that there's lots that we're learning, because, for years, there was lots of fasted blood samples. And then loads of the early sports nutrition research was done on fasted athletes. 


And I don't know, over the last 10 or 15 years, people started to say, “Well, this isn't how athletes participate. So many of these studies were then done in a fed state. And I think, increasingly, now we're seeing that in the nutrition world as well, recognition that the vast majority of what you eat, you do not consume on an empty stomach as your first meal of the day. So we're seeing more and more research. Look at the prime state where you've already had your initial meal. Looking at sequential meal tests and the postprandial response, because we pretty much spend the entirety of our waking day in a fed or postprandial state. If we’re thinking about the blood lipids, you could almost argue that many people spend 24 hours a day in a fed state and are almost never post absorptive or fasted. So yeah, that's a big growth area. We're seeing more research there and learning a lot of that.


[00:31:54] LB: Yeah, no, I'm definitely excited about that. That's plenty of topics to get into over the years. That's for sure. Because we're in sport and exercise nutrition, or sports science, strength conditioning, however, which way you look at it, we're very familiar with adaptations to training. We're familiar to things that may suppress performance in certain ways, things that will reduce or elongate time to fatigue, these sorts of things. These mechanisms – That we're delving deeper into these mechanisms that respond to stimuli, which absolutely could be training. Physical training is one thing. And we're now starting to go down this idea of nutritional training, whether it's train low, train high, eliciting adaptations to that, train low, increasing the impact that they will have on mitochondria, for example, blah-blah-blah-blah, and substrate utilization, and so on. And then more recently, we've even started talking about training the gut, for example. If we go really deep into that metabolic machinery, I imagine a lot of things are technically trainable, because it's just an adaptation to a series of responses, which are going to be chronic as opposed to acute. With the focus on this circadian rhythm sort of idea, this trainability of the circadian rhythm, is it set in stone from your perspective? Or is there a degree of trainability there? What are your thoughts?


[00:33:21] JB: These rhythms are certainly trainable. And we know that, based on evidence, because there are plenty of studies which demonstrate that whether you call it dysregulation or regulation, but individuals who are following daily patterns, which are more or less in line with recommendations will exhibit a phenotype which is better or worse matched to what they need. So we know that this is trainable based on evidence. But that also, again, it makes perfect sense, and is easily understandable. Because unlike other adaptations, if we think of the classical exercise adaptations, say, where you're trying to undergo mitochondrial biogenesis, increase the ability to utilize a sugars at the muscle, or even to gain more muscle with resistance training, those things arguably have more obstacles in the way, because we need to have the stimulus, which often would involve the nucleus seeing some gene expression. So we've flipped this switch, the recognition, that the body could be more suited to this activity. But that needs to now pass through to the whole body level. So we then also need to see some protein expression and then we need to accumulate and incorporate that protein and then find that at a tissue level and at a whole body level we've adapted. So for argument's sake, we actually would need to see a bigger bicep at the end of the day. You've had to make something. With all of the restrictions in place with that, were you stimulating the adaptation maximally at the right time and then providing the substrate to let it happen? 


Now, arguably, with the circadian timing system, we're not necessarily looking for a bigger net result at the end. We just need things to happen at a different time. So maybe on that more philosophical angle, it becomes more understandable why this might be trainable. Because it's entrainable. We can just shift our rhythm a few hours. And there's no greater overall grams per day cost for whatever nutrient we needed. It just needs to happen at a different time. And we know that the system has the capacity to change the clocks like that.


[00:35:36] LB: We're in danger of – This conversation, I can see, could go on for hours. So it's just mind bogglingly interesting to me. I hope it is to everyone else. But I guess where I want to go on this at this point is these rhythms and how they influence macronutrient metabolism. I know we've touched on some of this, but we've got lipid metabolism, we've got carbohydrate metabolism. Each of those conversations in themselves could be hours and hours and hours. But what, I guess, we've already established, it isn't necessarily a one-way process. Nonetheless, there is a significant influence or significant interaction that occurs that's going to be relevant to health and/or performance. Could you take us through that a bit, please?


[00:36:20] JB: Without putting kind of different organs and tissues in in rank order, we always have on the tip of our tongue, don't we? It’s the key metabolic tissues when we're thinking about something like exercise. Muscle, obviously being our engine room, that's going to be what is responsible for exerting your forces on things. And we know that the muscle is incredibly prone to changes in the rhythm of things. So in terms of whether we're talking about carbohydrate metabolism, lipid metabolism, or indeed protein metabolism, we find clear day-night rhythms in these things. 


And in our symposium review, we kind of listed through the individual nutrients, if anyone's interested in these specific responses, but as I mentioned, the exposure of that peripheral tissue then. Generally seeing more glucose in the morning and more lipid later in the day is consistent with how oxidation is going to change over the day. And then the other important tissues, the liver, probably will be the second I would mention. We know how critically important that is for homeostasis, generally. But particularly when we're thinking about athletes and exercise, it shows such a clear rhythm in being a carbohydrate reserved for exercise, I don't think gets as much attention as it should. I think many people read about exercise science, and will be forgiven for thinking that muscle glycogen is desperately important, which it is. But I think many people in this field, certainly when you're new to the field. I did. As an undergraduate, I thought muscle glycogen was so important because everybody's measuring it. But the reason we're all measuring it is because it’s safe and easy to take muscle biopsies. 


The fact that so few studies have really looked at liver metabolism, certainly not using muscle biopsies, isn't telling us that it's not important. It's just that it's really difficult to do. So they're really valuable the studies that we have a bit of done that. But just the same as with muscle, in our review, we broke it down for muscle, liver and, I think, adipose tissue, and showed that carbohydrate and fat and protein metabolism all show clear rhythms, which can be affected by both nutrition and/or exercise. Generally, as I say, we're thinking about higher glucose levels in the morning and higher lipid levels in the afternoon. 


One study – I think I may have talked about this on a previous podcast, but I can't remember. One study we did do where we took muscle biopsies around the clock. No exercise in that study, I should add. But we had people staying in our laboratory for 36 hours consecutively, and took a muscle biopsy every four hours. So I was incredibly grateful to our participants over that time. But that gave us one of these early looks at we applied lipidomics, which really means we were measuring the levels of various lipid metabolites over the period. 


And you see this really clear rhythm, where despite the fact our participants didn't get meals, it was just constant feeding, you find that the levels of gene transcript, so the gene expression, and also the levels of these actual lipid metabolites in the muscle, show a clear, what I call tick-tock. Interestingly, a lot of these things, four o'clock is the magic time. So you tend to have your lowest levels of the liquid metabolites at four o'clock in the morning and highest at four o'clock in the afternoon consistent with when your blood fats are highest.


[00:39:57] LB: Yeah, that’s fascinating in its own right. And potentially, from a different conversation about issues with sleep and various other things maybe, which I've got Neil Walsh coming on in not too distant future not to talk about immune health as we have in the past, but also about sleep and how that impacts health and various other things. So I'm going to ask him about that and see what he thinks. 


I guess, when we're talking about nutrition, metabolism, body composition, why we should bother altering our diet, our lifestyle and so on, that inevitably comes to the topic of, “Well, how's that going to affect my weight? Who cares about health? Let's talk about weight. Obviously, they're related one way or the other. And there are two topics that one tends to look at. And one, of course, is energy expenditure. And the other one is, from the other perspective, is the factors that influence why you feed yourself as much as you might feed. And I guess we'll tackle this next phase of this conversation in the same way, where what I'm interested in is what are the relevance of these rhythms to energy expenditure? Precede the conversation about appetite regulation, of course.


[00:41:08] JB: Yeah. So when we're thinking about energy expenditure broadly, we just have to remember that we're talking about three components. Resting metabolic rate, which is just your ongoing energy requirements. Diet-induced thermogenesis, which is how much your metabolism increases in response to a meal. There's varied evidence for a circadian rhythm for some of those aspects. But the physical activity energy expenditure is the one where it's certainly has the most capacity to respond to your feeding state, your sleep and all the other kind of time givers we might have. But there's very poor evidence for a clear rhythm in that other than just the natural, it's going to be higher when you're up and at work and your body temperature is higher, your heart rate is higher. But that's always interested me whether eating at certain times can adjust that. 


And so we – As I talked about on, I think, the first podcast I did with you, our breakfast study has shown that in lean and obese people, that if you skip breakfast, you will spontaneously cut down your physical activity levels. I'm really pleased that since that – I mean, the finding was really clear. Actually, it was a big difference in energy expenditure. But nonetheless, I'm really pleased that since then, several other laboratories have independently verified that. Cross-section research seems to show that too. We've done some other studies that have shown it. And then our most recent study we had, the lead off. It was Ian Templeman. We published this in Science Translational Medicine just last year, was doing alternate day fasting, where we had people either eat for 24 hours, or fast for 24 hours at a time. 


So while a lot of people talk about alternate day fasting, and there's many studies looking at that, the fasting days often didn't necessarily involve fasting. They were just low energy intake. But if you just have a few 100 calories every now and then, you might actually still not be in a fasted state. So we were kind of going for proof of principle here to really see if there is any effect of fasting. No one's going to be able to accuse us that this was not fasting we had people doing. They were going 24 hours without food at a time. I have then had a lot of people accuse us afterwards and say, “Well, this is useless. Who's going to do that in the real world?” So I hasten to add, “We're not trying to sell diet books here. I'm not recommending that anybody does what we did. But it was looking at the physiological mechanism.” 


And we did find, again, as we've seen in our previous studies then, that the participants who were trying to lose weight by fasting every other day, they did cut down their physical activity levels. So they’re kind of – Just like with our breakfast research, I don't believe it's that if you have breakfast, you suddenly join a gym and go and run for two hours. But it's the spontaneous low to moderate level activity that you almost don't notice you're doing. And we were able to measure that that is what's lower. If you miss breakfast, or if you fast for a whole day, you cut back on your energy expenditure a little.


[00:44:18] LB: Yeah. No, that's great. And that really helps a lot, I think. In sports science, sports nutrition, and so on, whatever textbook you pick up, or – Again, I've done podcasts about this. There's a lot of information and there's a lot of confidence in what we know about measuring things like energy expenditure and what's involved in expending energy. And we can plan our workouts with some degree of accuracy of if I'm going to do a 500-calorie workout, I’d be fairly close. 


And indeed, we can sit there and go, “Oh, all I've got to do is introduce a slight energy deficit and so on so forth.” But of course, what that doesn't really take into account is not so much the knowing or thinking you know what you should eat in terms of calories or whatever if you've managed to pin that onto paper or use your energy calculators and so on. It is that sheer human thing of a desire to actually eat one's appetite is a powerful thing. 


And for many people, that is such a powerful thing that it is the master and not the slave that brings about many of the problems that they have with obesity, potentially, or weight problems or whatever. At least that's a perception. That's an angle, or a concern. And there are various people have written works. I’m thinking Hungry Brain, for example, is an interesting book on this sort of topic. There are various other people that will suggest that there are various reasons why our appetite can be influenced by even something as simple as having a good day or a bad day. The emotional links that go there. But of course, there is also a link with the circadian rhythms, isn't there? What is that link? And why is that potentially important?


[00:46:04] JB: I think that human element is so important, because as you say, people have a drive to eat, per se. But at the same time, I feel that a simple public health message that's easy to understand, there's no need to calorie count. When we're talking about intermittent fasting, however you define that, or time-restricted eating as the other one, which is kind of depending on how you define it is a type of intermittent fasting. But the key thing that I take away from it, having seen lots of our participants go through these, is one thing you can't deny is that it's easy to understand what you're doing. You don't need to count calories. You don't need to know whether this food is healthy or high in fat. So you don't need a degree in nutrition. You need to be able to read your watch. 


So as long as you know, “I didn't get to eat till three o'clock today. Or I don't get to eat after three o'clock today,” people can do that. And the impression I get anyway is that, psychologically, that binary on-off decision of I don't get to eat. If a friend offers me a biscuit, I say no, because I don't get to eat till or three. I think people strangely find that more acceptable to adopt and adhere to than they would saying, “Right. Well, if I've had a biscuit now, that's this many points or calories. And now I can't have another one later.” It's like once you've opened the floodgates, you can't close them again. So I certainly think that in the human element, there's a sideway. Time-restricted eating is good. And then when we link that back, as per your question to the rhythms, the question is, “Where should that window be?” Arguably, I'm not such a fan of these kind of crono-type ideas where we, again, just dichotomize people into being morning larks or night owls. I'm not sure there's two types of people in the world and two only. 


But certainly, there are people who fall into one group or the other and say, “Oh, I couldn't live without breakfast. I'd rather miss dinner.” And some people the other way. And one of the other studies we mentioned in this review we just wrote, Harry Smith did a paper on sleep fragmentation and caffeine, where at the end, because the coffee before breakfast really seemed to have a negative effect on insulin sensitivity, I tried to apply a more pragmatic conclusion. Because I figured if we go ahead and say, “Don't drink coffee.” People don't want to hear that. 


But if we have the pragmatic conclusion that maybe just have your coffee after breakfast, then it can't interfere with your postprandial response. It was really quite strange. Because for every person who was just saying, “That's crazy. Who would drink coffee after breakfast?” There was another saying, “Well, you're crazy. Doesn't everybody drink their coffee after breakfast?” So I definitely think that there's people who naturally have very polar approaches to their nutrition in terms of time of day anyway.


[00:49:05] LB: Well, you raise an interesting point, which actually links to me personally, for example, where I love coffee. I’m far more interested in my coffee than I am in my breakfast. It’s partly a cultural thing. I was raised in a French house. Having coffee is important. It's also an opportunity to have a conversation. And my upbringing is my mother and I used to have chats over a coffee before school or whatever. And it was really – I wasn't drinking coffee as a six-year-old, by the way, or an eight-year-old. But there is that. We've talked about the human element. 


There are of course components here that relate to what people like and don't like and the practicality of it. And of course, we also need to – Bear in mind, you and I are both parents. James, there are certain things that you also need to fit with what works for everyone else. And I think I'm with you. I don't think we can just put everyone into a black and white you’re this, you’re an A, you’re a B. Because life isn't that simple. But also, there is potentially the fact that you may not have adapted to or found your appropriate type for whatever reason. But however which way we look at it provides us with opportunities. And so it goes from reading your paper. I hadn't known too much about these environmental cues, time cues, the zeitgebers, for example. 


So it's not just a question of what happens to be practical, because that will be an overriding factor for most people, I would imagine. But if they're going to take what the science tells us into account and what you've learned into account, I think these cues, these time cues, are useful strategies to help tweak our existing lifestyles. What are those cues, those time cues, those physiological opportunities, James? And are they relevant? Are they useful as a strategy? What are your thoughts?


[00:50:56] JB: Yeah. So there's all sorts of those cues. But when I have to come up – If I have to come up with a kind of league table, then top of the list is light exposure. So if people are just thinking of a checklist of which things need to align and which things could they use to help adjust their daily pattern or their daily rhythm? Then your light-dark cycle is important. So trying to get light exposure at the right time, as in daytime, when you're awake. And many technologies help us with that now. A lot of our phones and so on try and protect us from bright blue light that is going to wake us up at the wrong times. 


After light and being awake, I think nutrition comes in second. So making sure that during your awake phase, in the light is when you eat. And not eating at night. But I'll come back to that in a moment. And then again, linked to that, the next one, would be our restfulness and active cycles. So generally, for most people, when it's dark, so when we're on the side of the planet, not facing the sun, you don't want other artificial light shining your way. You want to be asleep. You want to be not eating. And that's when you have your rest. And then when you're in the sunshine, you're awake, eating and active. So that's the very simplistic way to look at those main time givers. 


But I think going back to that, I think I do still wonder whether you mentioned opportunities. And while there's a real focus, and I'm sure Neil Welsh will talk about this then about how the importance of sleep. And of course, we don't want to interrupt sleep unnecessarily. I do sometimes think of athletes who are, by definition, some of the most motivated and dedicated people we find, that if you tell them go for a two-hour run every day, go and sit in an ice bath. Think of all the things that athletes do, which are really very uncomfortable, but they do them because of their drive to compete. 


We're often dealing with someone who telling them, “Don't eat this food. Do eat this food.” That's the easy job for them. They're going to do that the exercise and the ice baths and everything. So having a nutritionist tell them, “Right, you're not having carbohydrate today. Oh, you have to ingest this supplement, which tastes awful, but will improve performance.” I think, in many ways, you could take an athlete as this is someone not just trying to have a healthy diet. They want an optimal diet. And that word optimal is always dangerous, because it means can't do any better. 


So if this person is following all the advice, they're doing what you're telling them, which isn't what you get normally if you're giving nutritional counseling to a general member of the public, the athlete will often do what they're asked. So let's say they're following. They’re eating the right amounts of food. They're eating the right types of food. They're spreading their protein across the day. They're doing everything as they should be during the day. And you're thinking, “Well, where is a further opportunity for marginal gain?” And that is the only reason I'm saying, “Hmm. Well, if they're probably following the advice for a good night's sleep, too, which we know is important for all sorts of things, does that also give us one more opportunity to intervene?” The only period of a day when an athlete is catabolic, post-absorptive is while they're asleep. 


Now, I'm not saying it is possible, but it's a possible opportunity. It could be that waking them up is just so harmful that actually we don't want to do that anyway. But there's a lot of people who wake up in the nighttime anyway. So maybe there is a way to say just waking up and having a quick shot of a room temperature supplement could be an opportunity. So could do more harm than good. But that remains to be seen. 


So I do think it would be interesting to see some more studies on nocturnal metabolism in athletes, either ingesting something, maybe something with a slower response before bed like casein or something. Or having people wake up at the middle of the night and having a quick shot and going back to sleep. Might even improve sleep, by the way. There're a few supplements where their sole purpose might be to help you sleep better.


[00:55:09] LB: That brings me back to something I like to talk about a lot, where things like the knowledge that we have on these things, the strategies that then become available, understanding the strengths and limits of those strategies. The tools in the toolbox is really what I refer to, whether it's a supplement or a strategy, is why it's important to understand this stuff, but also to understand the significance of it so that you can sit there and go, “I can do such strategy. But do I really think this is a good idea.” And that's what you have to weigh up, isn't it, in that thought process?


In that mindset of importance, we've talked about body composition. We've talked about nutrient timing and metabolic regulation a fair bit. But from an impact on health, specifically, obviously, a human being living in this world is pretty dangerous, particularly the time we're recording this, it's ever more dangerous, whether it's viruses or people trying to take over countries or wherever. But within the realms of nutrient timing and the impact that that realistically can have on your health where you're not losing sleep worrying about this sort of thing. I guess, in summary, what are your sort of concluding thoughts on this topic, and particularly as it relates to health, which is the more important focus, I guess, on this stuff?


[00:56:31] JB: Okay. I would say I'm comfortable saying that timing and the when we eat has been less researched than the amount we eat and what type of food we eat. And I'm comfortable saying that it's really important. I think it might not be as important as those other things. But it certainly has the potential to affect our bodies, and is one of the tools in our toolbox. So maybe that analogy is the way to go. It might not be your most important tool. It might be that your general lifestyle of when things happen means that that isn't practical. That you can't say I'm going to eat the same time every day. Because not everything else in your life happens at those times every day. But it's certainly important enough to understand it better and know how to not get it wrong, whether that's for health, or performance means. 


So I think, for a proper understanding of nutrition, those are your three considerations. For me, everything in nutrition comes under those headings, what you eat, how much and when you eat it. There's no consideration outside of that. So yeah, I think there's still a lot more to learn. And if I was kind of saying, “What are the things I think are the potential growth areas?” Just as I was maybe more pessimistic earlier about how soon we're going to get anything more on personalized nutrition, especially in relation to meal timing, the things where I think we're going to see more data, and if people are getting into research, it will be great to jump on the novelty, would be looking at sequential meals. So understanding the effect of feeding when you've already had a priming meal earlier on. And looking at the nighttime opportunity to eat or not to eat, it could be an opportunity for either.


[00:58:14] LB: Yeah. For me, on the personalized nutrition thing, and I know we've done – We had a good podcast all about that. And people should listen to that. I think it's still every bit as relevant as it is today. And I'll link to all of those podcasts that we've done and other relevant bits and all the papers and stuff we've discussed. But nonetheless, people are going, “Oh, that's all very well. Well, what about me? Me, me, me, me, me. My situation. Or my client’s situation.” As a nutritionist, somebody is paying me to provide them with individualized advice. 


And for me, personalization is where I've got all these different things I could do. There're too many things I could do with my client, my athlete. So for me, personalization is simply a question of I'm just prioritizing the various things that we could do into, like you say, a league table of priorities, which I feel are going to have the most significant impact that are healthy, are relevant, etc., in the time that's available. 


And there may be testing involved, but that might be something like I'm assessing someone's body composition, just to understand where they're at with their body composition, as opposed to maybe some of these novel tests that appear to be very scientific, etc. Whether it's genetic testing, or food intolerance testing, or whatever. But the reality is, is that the science may not – Well, is not there really, in my opinion, most of the people I've spoken to. But nonetheless, personalized nutrition is something you've mentioned, I've mentioned, is of great interest to people. And this, of course, is an area that, I guess, it's the other version of that word personalized. It's very personal to impact one's daily habits and lifestyle, isn't it? And however which way you look at it, having a greater understanding on this topic allows you to personalize your approach to nutrition. Or your prioritizing the importance of getting your lifestyle sorted, right? I mean, fundamentally, from your perspective, James, that is clearly something that is important for human health, isn't it?


[01:00:21] JB: Yeah. And I think this comes down to the semantics of personalization. You can take an individual in as a client. Their program is not going to be the same as everybody else's. So it's individualized. But often, when people use the term personalized, they mean some stable personal characteristic. Like, “ell, tell me my blood type. And that means I should eat more chips or something?” Or, “Can we look at my genetics? If we look at my genome and my microbiome – I'm going to give you all my vital statistics and you tell me what to eat for the rest of my life?” And that's not what I think is possible or will ever be possible. The phrase that we used in our review was that it's not about who you are. It's about what you do. So yes, you can personalize the program, but it's not on their stable personal characteristics. You would want to be measuring and monitoring constantly their personal lifestyle. What do you do? When do you do it? What are you trying to achieve? How did you respond to that at this time of day? And so the kind of measurements you want are not a snapshot of who they are that can be applied forevermore. It's about monitoring to see, “Well, okay. So you seem to get up at this time, and you're out in the light at this time. And then we're measuring your physical activity, and this happens. And you seem to have a few spikes in glucose at that time.” 


And again, I think that's a good news story, not just because it feels good to say that we're all more the same than we are different, which, especially at the moment is a message the world needs to hear. But it's also good, because if we had made that statement, if the genome had been sequenced earlier, and we'd realized how futile some of these diets based on genetics were 30 years ago, we wouldn't be able to give an alternative to those. But realizing now that we're not going to be able to predict diets just based on genetic information or something actually falls at a point in history where everybody is walking around being monitored the whole time. People are wearing – I see people wearing glucose monitors all the time. Physical Activity monitors, your phone, light exposure. So it's at a time when our free living lifestyle environmental influences can be monitored. 


And so I think there's a lot of potential in that trying to integrate that into, say, not just when you said you had carbohydrates at breakfast, your blood sugar's did this. It’s being able to match that up with, “Oh, hang on. Those were on the days you worked out or when you did these exercises.” So yeah, I'm not totally counting personalization, unless it's someone using that term to mean stable characteristics. I think we just need to model on other factors.


[01:03:12] LB: Absolutely, James. And you and I are on the same page on a lot of these things, which is why right at the beginning, we both feel it's important to define what we mean by certain terms and so on. And of course, that is just an example. It gets lost in translation. And of course, for those that don't have your background, in particular, in science and research, a lot of this stuff's very convincingly precise and accurate. Whereas the reality is it might have print out – You get a blood or a buccal swab sample or whatever and you get a nice fancy looking report from a lab, and it's extremely convincing. But the reality is, “Hmm.” Hence, knowing the strengths and limitations of this stuff. 


I have a running theme where I talk about – Yes, we use phrases like evidence-based all the time. But as a practitioner, I prefer the term evidence-informed practice, because I still need to be in there critically thinking about this stuff and deciding on the context. Is it actually relevant in this particular situation? That study was done on basketball players? Yes, but that was college basketball players. And I might be trying to apply this to the world's greatest elite basketball player on the planet. And he is absolutely an outlier as it relates to those college baseball players. So one is apples and the other one's oranges sort of conversation. 


So we could go on for hours and hours and hours. I know we could. You're a busy man. So I want to let you go and get back in the lab, basically, and help us learn more. But I'm going to, as I said, link into the show notes papers and podcasts and so on. But if people want to follow what you and your team are up to, is there a lab, website, etc., nowadays? How do we follow you guys?


[01:04:53] JB: So if you go to the Bath pages, then on the University website, we have a Center for the Nutrition Exercise and Metabolism, CNEM. Or my Twitter handle, which I expect they'll find through yours, since we were chatting earlier. But that's Dr. B Seam Jets. Yeah. And otherwise, I make sure I make as much noise as possible about the papers as they come out to try and make sure they achieve impact.


[01:05:19] LB: Well, great. Well, you've had plenty of impact over the years. And hopefully today, the listeners have been impacted by what we've talked about and the knowledge and perspectives you've brought to it. So on behalf of myself and the listeners, I'd like to thank you very much for your time today, James. I look forward to talking to you again in the very near future.


[01:05:37] JB: Yeah, you’re very welcome. And let's see if any of your listeners can come up with the clock with the fewest number of moving parts.


[01:05:43] LB: There you go. There's a challenge for the listeners. Find us on Twitter, and let's go for it. Okay. Thank you, James.


[01:05:49] JB: Thanks very much. Bye-bye.