Carbohydrate Availability and Exercise. Podcast with Javier Gonzalez.

Why is losing weight – and keeping weight off – such a puzzle?

Granted, obesity is a complex and multifactorial problem at the population level. But at an individual level, the root cause seems to be quite simple: it is chronic positive energy balance.

Simple, perhaps, but not easy.

We now know that alterations in energy intake or energy expenditure can activate ancient feedback mechanisms that have evolved to preserve energy balance. And unfortunately for us, this system doesn’t seem to be biased toward supporting our beach body goals. Instead, it is adapted for survival.

This is one reason why, for example, exercise interventions usually do not result in as much weight loss as would be predicted based on the projected energy expenditure produced by the activity. Changes in hormones like leptin, elicited by the energy deficit, cause hunger to ramp up. Consequently, studies have shown that many people who participate in structured exercise interventions wind up eating more food to partially or wholly compensate for the calories burned by that activity. You might have experienced this phenomenon yourself.

So, does this mean that exercise is a futile endeavor for managing weight? Actually…no. Not at all. Here is where the story gets a bit complicated.

It was recognized decades ago that people who are highly physically active tend to be leaner than counterparts with a sedentary lifestyle, but perhaps not as a direct result of higher energy expenditure. Oddly enough, it may be due to improved appetite regulation.

In the 1950s, researchers assessed caloric intake and body weight in a sample of 213 workers at a mill in West Bengal. These men were engaged in 16 different jobs that spanned a very wide range of physical activity, from sitting at a desk to hard physical labor. So they were looking at a group of people living in the same place, similar in many ways, but with patterns of physical activity that were dramatically different.

When these scientists diagrammed body weight by occupation, they found that men performing the most sedentary occupations (supervisors, clerks) were the heaviest. Hardly surprising.

For those individuals living in the sedentary zone, low activity was met with relatively high food intake. And they were heavier as a result.

These researchers, all the way back in 1956, concluded rather presciently:

This observation that energy balance seems to be better regulated in the context of physical activity has since been validated in more recent controlled experiments. For example, when researchers present blinded subjects with meals of varying caloric content, the participants who are habitually active do a better job of adjusting their subsequent energy intake (meaning, for instance, that they eat less at lunch after consuming a breakfast that is higher in calories). Similarly, putting overweight participants on a 12-week exercise intervention was shown to improve the accuracy of the appetite regulation system.

Okay, so let’s quickly summarize: metabolic responses to exercise tend to acutely increase hunger, and thus limiting weight loss. Hard to outrun a doughnut, right?

But at the same time, chronically high physical activity has been shown to enhance sensitivity of biological systems that regulate appetite. How do we reconcile these seemingly contradictory observations?

Our guest for this episode has a hypothesis that might explain this paradox.

In this episode of humanOS Radio, Dan speaks with Javier Gonzalez. Dr. Gonzalez is a professor at the Department for Health at the University of Bath in the UK. His research seeks to understand the interactions between nutrition and exercise in the context of health and disease.

One component of this work is uncovering dietary approaches to influence the production of hormones from the gut, as a means to regulate appetite and energy expenditure. Another strand of his research, which is the focus of this show, is exploring the underappreciated role of carbohydrate availability in the regulation of energy balance and metabolic health.

What do I mean by carbohydrate availability? Well, our storage capacity for carbohydrates is relatively minuscule, compared to fat stores – even on a very lean individual. Think about it: a normal healthy person might store less than 1200 calories as carbohydrates, but they could store in excess of 100,000 calories in the form of adipose tissue! These stored carbs can be depleted much faster, and several studies suggest that alterations in carbohydrate availability may be carefully monitored by the body as a gauge of energy balance.

For instance, a metabolic ward study demonstrated that four weeks on a ketogenic diet resulted in a reduction in plasma leptin levels by about 20%, compared to a high-carb diet with the same number of calories. Lower leptin, all else being equal, usually results in greater appetite, and is a major nemesis for people who are trying to maintain weight loss.

But high physical activity levels – and accompanying high physical fitness – produces relevant changes in carbohydrate and fat metabolism. For instance, we know that people with high aerobic capacity have enhanced muscle glycogen storage capacity, and they don’t use up as much muscle glycogen during exercise. This could go a long way toward explaining why people who are more active and more fit seem to have tighter control of energy balance – and might be better able to rein in their appetite after a bout of exercise or after a larger-than-normal meal.

To learn more about Javier’s fascinating hypothesis, and his work in general, check out the podcast below!

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Javier Gonzales - 00:01: It may be that the liver and the muscle carbohydrate stores respond differently, and one of those stores may be more important than the other in terms of maintaining energy balance.

Dan Pardi - 00:16: Hello everyone, welcome back. Today, I would like to welcome Javier Gonzales to humanOS Radio. Dr. Gonzalez is a professor at the Department of Health at the University of Bath in the UK. His research seeks to understand the interactions between nutrition and exercise, all in the context of health and disease. One component of his work is uncovering dietary approaches to influence the production [inaudible 00:00:39] as a means to regulate appetite and energy expenditure. Another strand of his research, which we will be discussing today, is exploring the role of carbohydrate availability in the regulation of energy balance and metabolic health.

00:52: Obesity at a population level is obviously a complex and multifactorial problem, but the root cause at an individual level is relatively simple, it's a chronic positive energy balance. Simple perhaps, but not easy. Part of what makes losing weight so difficult is the alterations in energy intake or energy expenditure. They can activate feedback mechanisms that have evolved to preserve energy balance. This is one of the reasons why, for example, exercise interventions often do not result in as much weight loss as would be predicted based on the energy expenditure produced by the activity. Changes in hormones elicited by the energy deficiency cause hunger to ramp up, and thus you eat more food to partially compensate for the calories burned by the activity.

01:33: But somewhat paradoxically, it has been known for a long time that people who are highly physically active tend to have better energy balance appetite regulation over the long haul, and they do tend to be leaner than sedentary counterparts. The regulation of energy balance in response to physical activity is not straightforward. My guest today wrote a paper which lays out a novel hypothesis that elegantly explains both of these phenomenon, which is why I'm looking forward to our discussion today. So Javier, welcome to humanOS Radio, and before we dive into your review and your hypothesis, tell us a little bit about your background and how you became interested in nutrition and exercise and energy regulation.

Javier Gonzales -02:09: Yeah, thank you very much for the invitation. I first got interested in exercise metabolism as an undergraduate student. I was a keen, I wouldn't say athlete, but keen recreational athlete and used to be a keen rugby player. So I was interested in personally how I could improve my performance really through primarily nutrition, and so I did a sport and exercise science degree, in the UK that's, I guess, equivalent to a kinesiology degree, and found it fascinating when we were in the lab and finding out how nutrition could have quite a potent effect on performance.

02:39: And I particularly remember one lab in my second year when we ingested sodium bicarbonate, and I was the participant and could really feel the difference then when I was performing high intensity exercise. And that sparked an interest in trying to understand what's going on. How can something that seems so simple, some cheap sodium bicarb, have such a potent effect on performance? That led me to do masters [inaudible 00:03:01] research and then onto a PhD and I was always fascinated by carbohydrate and fat metabolism. So ever since then I've been studying various approaches through meal timing, breakfast and fasting, that could influence exercise metabolism and conversely how exercise can influence our responses to food intake. So that's probably the main way into what I'm doing now, and much of my work is focused on how dietary carbohydrate influences exercise, but also how physical activity influences our responses to carbohydrate and fat intake.

Dan Pardi - 03:32: My own experience with studying bicarbonate has been remarkable too. It's my favorite ergogenic aid. You take it before exercise, and you just simply feel better, particularly at the higher peaks and towards the end of the exercise bout. It's a really remarkable, simple intervention to improve exercise capacity.

03:48: We all know that obesity fundamentally is a product of sustained energy balance. Could you explain the components of energy expenditure that determine energy exiting the system?

Javier Gonzales - 03:57: When we start off, we should really break it down into the three main components of energy expenditure, the first being resting metabolic rate, and that's the energy that we are using just to keep all of our tissues and cells alive when we're completely rested and also in a fasted state. And the primary determinant of resting metabolic rate is just how big we are, so the bigger you are, the higher your resting metabolic rate because you've got more tissue mass to sustain. And within those different tissues, it's our lean mass, our muscle mass, our liver, that are the most metabolically active organs, and because muscle mass by mass is the largest, then that is the primary determinant of our resting metabolic rate. So the more muscle mass you have, the higher your resting metabolic rate. And as a rule of thumb, you can estimate that at around 13 kilocalories per day per kilogram of fat free mass, so for every kilogram of fat free mass, you've got approximately 13 kilocalories per day of energy expenditure.

04:57: Now, the second component is dietary-induced thermogenesis, also termed the thermic effect of feeding. That is the energy that we expend when we're digesting, absorbing, and metabolizing the food that we eat. All those processes require energy, and that's part of the reason that you get the meat sweats after you eat a meal high in protein, because you've got that elevation in energy expenditure and part of that is given off as heat when you're eating a meal. So that can vary between individuals depending on, for instance, digestive system and our metabolism, but the primary factors that dictate dietary-induced thermogenesis are the types of foods that we eat, so that's the macronutrient composition. Fat, for example, has a relatively low dietary-induced thermogenesis, and about between 0% and 3% of the energy that you've eaten as fat is, if you like, wasted via dietary-induced thermogenesis. So we're very efficient at storing the fat that we've eaten.

05:53: Compare that to carbohydrates, and that's got a slightly higher thermic effect, around 10% or so, maybe slightly higher. Proteins even higher again, so it can be up to 30% of dietary-induced thermogenesis when we ingest protein, and that's part of the reason why the meat sweats tend to happen more with meat, and they give them that name, because with high protein foods you get an even higher energy expenditure.

06:16: We often forget about the fourth component of the diet from which we can derive energy from, and that's alcohol. That also has a dietary-induced thermogenic factor. That's a bit more complex because it actually depends on how quickly you're drinking that alcohol. So if you have, for example, one beer and you're sipping away at it, then the main pathway that's being utilized has a thermic effect of around 12% or so, so reasonably at least less efficient than fat. But if you drink your beer more quickly and you saturate that pathway, then you go into a separate pathway of alcohol metabolism and that has a higher thermic effect, and it can be up to 30%, so similar to protein intake. But I should say I'm not encouraging binge drink, it's just an interesting notion there.

Dan Pardi - 07:02: I think I [inaudible 00:07:03] have experienced meats sweats, it might have been with a higher alcohol beverage and a steak.

Javier Gonzales - 07:06: Yeah. Yeah, yeah, yeah. So I don't know if you have the saying in the US, but we also have the saying of a beer coat. So when it's cold outside, and you've had a few beers, then you feel slightly warmer, so maybe that's where that comes from as well.

Dan Pardi - 07:17: Interesting.

Javier Gonzales - 07:18: So that's dietary-induced thermogenesis. And I should actually say that, in addition to macronutrients, there are other components of the diet that influence that. So, for example, if you've got highly processed foods that have been recently reported in a few studies, then you tend to have a lower dietary-induced thermogenesis in response to those foods when compared to, if you like, less processed foods. They're more difficult to digest and absorb, as you can probably imagine.

Dan Pardi - 07:42: Mm-hmm (affirmative). Or are they easier, so there's less work for the body to do?

Javier Gonzales - 07:46: Sorry. Yeah, the less processed food is harder to digest in [crosstalk 00:07:49].

Dan Pardi - 07:49: Right, right. And so your body burns more energy consuming those. Yeah, that makes sense.

Javier Gonzales - 07:53: Exactly. And then the final point is physical activity energy expenditure, and it's actually the part of energy expenditure, and actually a major component of energy balance, that is hugely variable between individuals, and it also varies day to day within an individual. So it's the part of energy expenditure that we can manipulate the most. Many people might use physical activity and exercise to try to manipulate their energy expenditure to induce weight loss, but those efforts can sometimes be or seem wasted, as we'll probably come onto in a moment.

08:26: But in terms of physical activity, it's probably important to emphasize that physical activity is different to exercise. Often when people think of physical activity, they think that exercise is the same thing, but an important distinction is that physical activity is all of the energy that we expend when our muscles are producing force. So normally that's when we're actually moving around, but it could actually be an isometric muscle force production. Take, for example, if you're doing a plank position in the gym, then you're still expending more energy than you would be at rest because those muscles are consuming energy. So physical activity encompasses everything from fidgeting all the way through to marathon running.

09:05: The definition of exercise is a sub-component of physical activity, and it's really a social construct, if you like, because the only thing that distinguishes exercise from physical activity is the conscious decision to be doing exercise for a reason. So we normally consciously go out for a run, and that would be our exercise. Now the important point around that relative to this conversation is probably that for most people with exercise, they can't burn enough energy to offset a lot of energy dense foods that they eat. So, for example, an average person might only be able to expend 400 to 500 calories per hour with exercise. But with physical activity across the whole day, which encompasses everything in your daily life that you don't even realize you're necessarily doing, that can amount to a couple of thousand kilocalories of energy, so that then is much more meaningful for energy balance.

Dan Pardi - 09:55: So if you, let's say, have a very sedentary lifestyle and you do a morning exercise bout, that can burn fewer calories than somebody who does not "exercise," but they have a very active day? They're standing at work, they're lifting, walking a lot, just because of the time.

Javier Gonzales - 10:10: Exactly. And I guess in recent times we're becoming a little bit more aware of that with most of the watches nowadays can capture a bit more of that extra physical activity, whereas 10 years ago or so then, we probably wouldn't even think that we were being so physically active in our jobs.

Dan Pardi - 10:24: Let's move to energy regulation versus just ways that we are expending energy. Part of the reasons why modifications to either exercise or diet by themselves are ineffective is because the body has feedback mechanisms that have evolved to preserve energy balance. Describe how that works and some examples that people can sink their teeth to do.

Javier Gonzales - 10:43: I won't cover too much of the evolutionary perspective because I believe you've had Herman Pontzer on before, who might have discussed some of this interaction whereby-

Dan Pardi - 10:50: That's right.

Javier Gonzales -10:50: ... with very high energy expenditures, we get some feedback where our resting metabolic rate and other processes might slow down. But the general idea is that if you manipulate one component of energy balance, that doesn't just happen in isolation, and the other components of energy balance respond and might counteract our efforts. Normally it's our efforts to lose weight, where we're trying to induce a negative energy balance, there's other factors that erodes that energy deficit. Now, a few examples of that might be if we try to restrict our energy intake to induce a negative energy balance, then what can happen is our spontaneous physical activity levels can actually drop down, so then we might actually achieve a neutral energy balance again.

11:33: And another aspect that can respond to that is also our resting metabolic rate, so that's going to respond in two ways when we cut our energy intake. Firstly, we're going to start to lose body mass. We're going to lose fat mass, which is obviously our goal, that's going to drop our resting metabolic rate slightly. We'll also probably lose some lean mass as well, which will drop our resting metabolic rate. But even if you account for that, you can get a process known as metabolic adaptation, whereby adjusting for that loss of fat free mass, we still get a downregulation of our resting metabolic rate. It's not huge. Kevin [inaudible 00:00:12:05]'s done some work on this to suggest that it's probably not important for the maintenance of weight loss because it's a relatively small difference in the context of energy balance, but it's there nonetheless. There is a process in the body that is downregulating our resting metabolic rate when we've cut our food intake, and that's defending against the loss of body mass. You can think of it as our bodies are constantly trying to maintain the current body mass that it's at.

Dan Pardi - 12:31: So these homeostatic mechanisms will tend to cause energy intake to match with energy expenditure over time, slowing or stopping fat loss. But research has shown that highly active individuals are usually leaner than sedentary counterparts, so does this suggest that higher levels of energy turnover may be able to overcome some of these mechanisms to some degree?

Javier Gonzales - 12:49: Perhaps. So the first evidence for this that really drove the hypothesis behind this was in the 1950s, where this group studied some workers out in Bengal, and they classified them for their physical activity levels based on the type of jobs they had. So if they had a lot of manual work, they'd be classified as highly physically active, whereas if they had less labor-intensive jobs, they'd be classified as less physically active. What they found was that, at a moderate level of physical activity, there was a given body mass. If people's physical activity was higher than that, then their body mass didn't increase, it was level, comparable to the people with a moderate physical activity. But if people had less physically demanding jobs, then they turn term this the dysregulated zone of energy intake, so the people with less physically demanding jobs had higher body masses and they had a higher energy intake.

13:41: So essentially if you take a moderate level of physical activity upwards, then the increase in energy intake is proportional to the increase in energy expenditure, and people seem to have more appropriate energy balance regulation. Whereas if you go to very low levels of physical activity, it's been turned this dysregulated zone where we don't regulate our energy intake as well as we might do at other levels.

14:04: So that was just an observational study back in the 1950s. Of course, we don't know if that's cause and effect, but more recently actually there's been an interesting study published in Germany where they've performed a randomized crossover design within a room calorimeter and they've manipulated people's energy balance, so they've studied them at high and low levels of energy turnover or energy flux. And the findings are perfectly in line with those previous observational findings. So there's reasonable evidence now, I think, to suggest that our energy balance regulation is better, if you like, at the higher levels of physical activity compared to very low levels.

Dan Pardi - 14:40: In the first part of your review, it deals with the metabolic responses to exercise and how that influences the amount of weight loss that might result from exercise, and the major player in this is the hormone leptin. What is leptin and how does it affect appetite and energy intake?

Javier Gonzales - 14:55: Leptin is a hormone that is mainly secreted from our adipose tissue or our fat tissue, and that, in a way, in the homeostatic sense of maintaining body mass, seems completely appropriate, at least from teleological perspective. Because of course the more fat mass we have, then the more leptin that fat mass will secrete, and that should then decrease our energy intake and restore us to a normal level of fat mass. So leptin suppresses our appetite.

15:23: It doesn't seem to always serve that purpose. It actually seems to respond more to a decrease in fat mass. So when we decrease fat mass, we get a fall in leptin and our appetite increases, whereas if you increase leptin concentrations in a general population, either directly or as a consequence of an increase in fat mass, then the suppressive effects on appetite don't seem quite as potent. So this doesn't seem to be working in the way we'd like in that it seems to respond more to a deficit than a surplus.

Dan Pardi - 15:54: So this see-saw, it's stronger on the deficit side. It can elicit physiological mechanisms that will preserve the fat mass on your body better than it will help defend against weight gain.

Javier Gonzales - 16:05: Exactly. And there's a number of interesting ways in which leptin's regulated. So it's primarily regulated by the amount of fat mass you have, so the more fat mass you have, the greater your leptin concentration. But independent of fat mass, it's also influenced by a number of other things, and one of those is probably high insulin concentrations. So, for example, when this first came to realization was that in studies where people were undergoing bed rest, so they were reducing their physical activity to a minimal level, that there was an increase in leptin concentrations over about seven days of bed rest independent of changes in fat mass. So they maintain their energy balance over those seven days, they don't gain any more fat mass, and yet their leptin concentrations rise. And what's probably going on there is that due to the bed rest, they're becoming a little bit insulin resistant. That leads to a compensation where we get higher insulin concentrations, and we know that if you infuse insulin into people at relatively high concentrations over a prolonged time, that increases leptin secretion from adipose tissue.

Dan Pardi - 17:11: Would increasing energy expenditure through higher activity cause leptin to fall in the same way that eating less does?

Javier Gonzales - 17:16: That's a really interesting question, and one I wish we knew the answer to. We certainly know that if you restrict food intake, you get a fall in leptin. If you do exercise training over a period of months and you lose body weight, then you'll also get a fall in leptin. There is a suggestion that you might be able to maintain leptin concentrations if you maintain food intake, specifically relatively high carbohydrate intake, but that's certainly not definitive evidence and we need more work in that area. An additional point is that a few studies that have put people on relatively low carbohydrate diets, independent of energy balance, they're maintaining energy balance, then a lower carbohydrate diet also seems to reduce leptin concentration slightly.

Dan Pardi - 17:59: So exercise can cause a drop in leptin, which can cause people to eat more, meaning that they lose less weight than they would have predicted through the energy expenditure of exercise. What do you think causes this decline in leptin concentrations? Is that known?

Javier Gonzales - 18:11: I don't think we know that yet. Certainly part of it is the reduction in fat mass with exercise training, but whether we can modify that through diet or other means and still gain the fat mass loss, that's the part that is the million-dollar question.

Dan Pardi - 18:26: Do some people show more or less change to their leptin concentrations given the same bout of exercise?

Javier Gonzales -18:31: They do, so if you prescribe people to exactly the same amount of exercise and you supervise them through it, people will respond differently in terms of their leptin concentration, but that might be because they've also responded in a different way in terms of their energy intake and the amount of fat mass that they've lost. So we don't know if it's a direct effect of the leptin. Some people may have compensated more in terms of their food intake, whereas other people may have exercised and not compensated with food intake, and that might have driven the leptin response. So there certainly are individual differences, but the direction of that effect driving it, we're not really sure on.

Dan Pardi - 19:08: All right, so leptin doesn't just respond to energy flux, it also responds specifically to carbohydrates and things like insulin. That's very interesting. Does this suggest a potential advantage to higher carbohydrate intake or even just refeeds that are relatively high in carbs after a bout of exercise?

Javier Gonzales - 19:22: That's kind of the hypothesis we're proposing, but it certainly needs testing, and I would say that all of this should be considered on a background of a lot of other factors going on. So leptin is only one hormone that influences appetite, there are many other hormones that also influence appetite, and there are many other non-hormonal factors that also influence appetite. So even if we can maintain leptin concentrations by perhaps feeding carbohydrates throughout or immediately post-exercise, then that might completely offset all of these other things that might be important for appetite. So this really needs to be taken in the context of broader picture.

20:00: Nevertheless, a few studies that have [inaudible 00:20:03] this do suggest that if you give carbohydrate during an energy deficit or during exercise, then it may be able to prevent the fall in leptin concentrations.

Dan Pardi - 20:12: And is that proportional to the balance of energy expended and consumed?

Javier Gonzales - 20:17: It's probably proportional to specifically the carbohydrate balance. So when we exercise, we mainly carbohydrate and fat, we burn a small amount of protein, so it's mainly carbohydrate and fat that we utilize. And the sources of those are fat from adipose tissue and also from our intramuscular stores, and the carbohydrates are coming from plasma glucose, which is essentially originally from liver glycogen and liver gluconeogenesis. So the liver is producing glucose, but the majority of carbohydrate use, especially at moderate to high exercise intensities, is muscle glycogen utilization. And we can influence that fuel mix either with diet or with exercise intensity and some other factors. Given that we are hypothesizing that carbohydrate availability is the primary factor here that's driving leptin concentrations other than fat mass, then it would be the carbohydrate balance of exercise that needs to be maintained.

Dan Pardi - 21:11: Carb storage capacity in the form of glycogen is very limited compared to fat mass, so how does this disparity play into energy balance? And obviously we can consume a diet that has relatively the same percentages of calories from carbs and fats, but what we store is quite different.

Javier Gonzales - 21:26: Exactly. And one of the reasons why ultimately whatever diet you're on, it all comes down to energy balance, because if you overconsume any macronutrient, we can only really store excess energy in any large quantity as fat. So if you overconsume fat, it'll end up as fat. If you overconsume carbohydrate, given enough time, it'll also be stored as fat.

21:48: Just to break it down a little bit more. If we consider our carbohydrates stores, then our liver can store a relatively small amount of carbohydrate as glycogen, and the evidence would suggest the maximum amount you can store there is about 500 calories or so. In terms of our muscle glycogen, it's stored in a lower concentration, but we've got more muscle mass compared to our liver, and the maximum we can store there is less than 3000 calories. So add that up together, and it's less than 3,500 calories of energy as carbohydrate. Compare that to the energy we store as fat and it is absolutely minuscule. So someone who's been essentially starved for six months would still have over 23,000 calories of energy stored in fat tissue. Take it to someone who's obese, and they might have over 700,000 calories of energy stored as fat, so the difference is absolutely huge.

Dan Pardi - 22:43: So a difference potentially between 3,500 calories all the way up to 700,000, so huge differences in energy availability. Okay, so we have limited ability to store carbohydrates, we store it as glycogen in muscles and the liver, how does the utilization of glycogen influence energy intake compensation?

Javier Gonzales - 23:01: Now this is a controversial point, mainly because it's difficult to assess. So it was first proposed in about the 1980s by JP Flatt, this theory, it was called the glycogenostatic theory. The idea was because these glycogen stores are so small, they need to be tightly regulated, especially our liver glycogen. That's supplying our brain with glucose when we're fasting, so it's a relatively important store of energy. The idea is that if we need to regulate our carbohydrate stores tightly, that maybe if we're in a carbohydrate deficit, there's going to be homeostatic mechanisms that aim to restore carbohydrate balance. That might be through increasing appetite, maybe specifically for carbohydrates, but maybe for total food, that ultimately leads to restoration of carbohydrate balance.

23:49: That theory was proposed in the 1980s, and there were a few rodent studies that seemed to support that, but then there was a series of studies in the 1990s in humans, and they were really well controlled. The initial one actually supported that hypothesis. So what they did is they got a group of Cambridge University students, and they put them in a room calorimeter for seven days, so they were studied in this really tightly controlled environment. For those seven days they were put on different diets, either low carbohydrate, high fat; moderate carbohydrate, moderate fat; or high fat, low carbohydrate. And what they found was that the high fat, low carbohydrate diet led to a higher energy intake over the seven days, and greater fat gain and body mass gain too. Whereas the lower carbohydrate diet had the opposite effect.

24:35: So that seemed to be consistent with this idea that the carbohydrate availability in the diet was driving energy intake, and if people were getting sufficient carbohydrate density in the diet, then they didn't have to eat much of that diet in total so they maintained energy balance. However, one of the factors that was also manipulated in that study was the energy density of the foods. And fat is one of the most energy dense of the macronutrients, around nine calories per gram, whereas carbohydrate has less energy density. It's only around four calories per gram.

25:08: So energy density, we know, is a major driver of energy intake. If you're eating a diet that, again, is quite processed, then it's likely to have a high energy density, so you're consuming a lot of calories in a small portion. And when they repeated that study, but this time matched for energy density, they didn't find that effect at all. So the effect in the previous study was probably entirely driven by the energy density of the diet, and therefore this glycogenostatic theory kind of lost tack in the 90s, and it wasn't really directly followed up. And part of the reason is maybe that was total carbohydrate balance in the body, and it may be that specific tissues, maybe the liver and the muscle respond differently. So when they matched for energy density, that effect was completely lost, and the previous work was probably entirely driven by energy density, so their findings actually countered this glycogenostatic theory. And it lost its way, people stopped researching it in the late 1990s or so.

26:06: Part of that might have been because they were only measuring whole body carbohydrate balance, and it may be that the liver and the muscle carbohydrates stores respond differently, and one of those stores may be more important than the other in terms of maintaining energy balance.

Dan Pardi - 26:21: Hepatic glycogen status seems to be more likely to influence energy balance versus muscle glycogen. What specific mechanisms might be at play, if that is indeed true?

Javier Gonzales - 26:31: And again, we do need more work on this. This is a relatively new area. Some rodent studies do support that idea. So if you take mice, for example, and you manipulate their liver glycogen content by genetically upregulating the amount of liver glycogen they have, which means that under both fasting and fed conditions, these mice have higher liver glycogen content than your normal mouse, then those mice are more physically active and they also spontaneously reduce their energy intake.

26:59: Furthermore, if you hepatically vagotomize them, so essentially you cut the vagal nerve that links the liver to the brain, that completely abolishes that effect. It suggests that liver glycogen in some way is signaling via the vagal nerve to the brain to influence energy balance behaviors. But of course mice aren't men, and we need to study humans if we really want to understand human energy balance. That's not just because energy balance is regulated very different in humans than rodents, we have much more social interactions and we're influenced by other factors, but also liver glycogen responds very differently too. So, for example, if you put a rodent on a low-carb ketogenic diet, its liver glycogen content will initially fall. Give it a few days or so, and it can actually restore its liver glycogen without consuming barely any carbohydrates. And that's probably because they've got a really high rate of gluconeogenesis, and they've also got a large liver relative to the rest of the body.

27:56: Whereas in humans, if you put them on low-carb diets, ketogenic diets, the studies that did this actually, they were consuming less than 10 grams of carbohydrate a day, which is really extreme. I've never really heard of anyone doing that nowadays. They also took liver biopsies directly, which is challenging and rarely done now for at least nutrition research. What they found was that people's liver glycogen content falls, and it remains essentially zero up to nine days on a low carbohydrate diet. So in humans it seems like we need to eat carbohydrate to restore liver glycogen, and liver glycogen responds very differently in rodents compared to humans.

28:35: And that led us to do some of our own work on this area. It is tricky, as I say, to measure anything going on with the liver in humans. You could take liver biopsies, but that's rarely done, and [crosstalk 00:28:46]-

Dan Pardi - 28:46: [crosstalk 00:28:46].

Javier Gonzales - 28:46: ... and you basically take your needle and go through the ribcage, which I wouldn't fancy myself.

28:53: The second option is you can measure liver glycogen using magnetic resonance imaging. You can adjust an MRI scanner, and it's actually known as magnetic resonance spectroscopy. So that's a really nice tool to noninvasively measure liver glycogen, but it's very, very expensive and can only be done at a few labs around the world.

29:11: A third option is to indirectly measure what's going on in the liver using metabolic traces, and that's what we used in our study. We use deuterium-labeled glucose, we infused it into a vein, and with that you can get a good estimate of liver carbohydrate metabolism. So we used that to measure people's hepatic glucose production during exercise, and the differences between people then will be mainly due to differences in liver glycogen breakdown. So people with higher liver glycogen breakdown during exercise in our study seemed to compensate more after exercise with higher energy intake. That was, again, perfectly in alignment with this rodent model, suggesting that maybe liver glycogen metabolism is a regulator of appetite and energy intake.

Dan Pardi - 29:55: Is liver glycogen spared during exercise? So will you utilize muscle glycogen? It makes sense because it's obviously producing energy at the source where it's needed most, but is there also some other mechanisms that are trying to preserve liver glycogen in the face of higher energy expenditure levels?

Javier Gonzales - 30:10: Yeah, so both liver and muscle glycogen show dose-response relationship to exercise intensity, so if you increase the intensity of exercise, you'll be utilizing liver and muscle glycogen more quickly. It seems to be a bit more exponential with muscle compared to liver. So with liver, it's a bit more of a linear relationship with exercise intensity, with muscle, as you increase exercise intensity, there's a disproportionately higher increase in muscle glycogen breakdown.

30:37: Now, I should say also that this theory that liver glycogen metabolism may relate to appetite, we don't know whether it's the absolute amount of liver glycogen that's there or whether it's the turnover of that liver glycogen that's important. So this is important for application, to understand that mechanism, because if it is about the turnover, and it may be that a high rate of liver glycogen turnover and breakdown is the stimulus for increased appetite, then that might mean that low carbohydrate diets are a good thing for controlling appetite and energy intake. Because once our liver glycogen stores have reached a low level, the turnover rate is slowed down, we're not utilizing the carbohydrate, and if that's the signal, then we're probably going to be in a better place to control appetite. But we absolutely don't know anything about that, and it's a really hot area to study.

Dan Pardi - 31:26: One potential mechanism you've mentioned so far is the fact that liver has neural afferents from the vagus nerve possibly detecting signals of either concentration or turnover of glycogen that could be signaling or effecting energy balance. Are there any other bloodborne factors that might be at play here?

Javier Gonzales - 31:41: The other is endocrine signaling. One that we've particularly focused on is fibroblast growth factor 21 or FGF21, and it seems to be suggested to influence by carbohydrate intake, and specifically sugar intake. So some of the rodent studies suggest that FGF21 is secreted by the liver, specifically in response to fructose and some of the simple sugars, and that would be consistent with hepatic carbohydrate availability because fructose is a potent stimulus of hepatic glycogen synthesis. If you ingest fructose, especially in combination with glucose, that drastically increases liver glycogen concentrations when compared to other types of carbohydrate. And if a high hepatic glycogen availability is the stimulus for FGF21, then that seems to all make sense. Also, that might be the link to appetite because FGF21 seems to influence appetite in general, maybe having a specific effect on carbohydrate intake.

32:39: There's a bit of genetic evidence in humans where some of these genetic variants in FGF21 are associated with their reported intakes of sweet foods. That's very preliminary evidence. One of the most challenging areas to study, in my opinion, in nutrition is energy intake and food intake because when we're reliant on self-report then we're on quite shaky grounds, but nevertheless, that's consistent with some of the rodent work where FGF21 seems to regulate sugar and carbohydrate intake. So that all seems to make a nice story, but at least in this one study that we've done so far, that didn't seem to add up because the FGF21 seemed to respond in a completely different way than would be consistent with that theory. So if liver glycogen was an important link to appetite with exercise, then it's probably not explained by FGF21.

Dan Pardi - 33:29: Do you have any hypothesis currently about the intensity of exercise simply versus the quantity of physical activity being an important factor here in affecting the sensitivity of appetite so that it's better matched with expenditure? So you end up having very tight control over how much you're taking in. We see that observationally that athletes are both leaner. Even though they might be consuming more calories because they're burning more, it's better matched to what actual expenditure is. Does intensity matter?

Javier Gonzales - 33:55: It's a great question, and there's a bit of work on this where if people perform sprint interval training or high intensity interval training, and if you compare that to your continuous moderate intensity training, then typically what you find is that with a moderate intensity exercise there isn't an immediate increase in appetite, but there might be over 24, 48 hours or so or longer. But with the high intensity interval training, appetite seems to be suppressed to a greater extent, but that's when you don't match for total energy expenditure.

34:24: In some of the other studies where they've done exactly the same, but this time they've matched the two bouts of exercise for total energy expenditure, then there doesn't seem to be so much of a difference in appetite. My current understanding of the literature is that if you match for total energy expenditure, there's actually no difference depending on the intensity of exercise, but we probably do need more work there, to be sure.

Dan Pardi - 34:46: Let's say you have somebody who is unfit who starts a physical activity program, who gets on the treadmill five days a week and walks for an hour. Would that yield similar benefits as somebody who burned the same amount of calories with the same degree of starting fitness but actually improved their fitness through higher intensity training?

Javier Gonzales - 35:00: That's a great question. One of the points we speculate in the review is that people who have a higher level of fitness might be more protected against the compensatory increases in energy intake with each exercise session. With a single bout of exercise, if we assume that carbohydrate is a major driver of energy intake, then we deplete our glycogen stores with every single exercise session and then we compensate afterwards, to some degree, more or less. Now, if you have a high level of fitness, you have less of a reliance on carbohydrate use during exercise and more of a reliance on fat use, which means that with each exercise session, you're using your glycogen stores much more slowly, and maybe therefore you don't compensate as much with appetite and energy intake. There is some evidence that people who are fitter don't show as much compensation.

35:51: The other factor that might play a role is that as you perform regular exercise training, you also increase your capacity for liver and muscle glycogen synthesis when you eat a meal. So if you take someone who's got a high level of fitness, you give them a hundred grams of carbohydrate, compared to someone who has a low level of fitness, you also give them a hundred grams of carbohydrate, the person with a higher level of fitness will store more of that carbohydrate as glycogen. And if that is a signal for satiety, then, again, post-exercise when the fitter person has the same meal, they're going to feel fuller and their appetite is going to be suppressed to a greater extent.

Dan Pardi - 36:27: You could imagine if you're depleting your glycogen, the compensatory mechanisms that would make liver glycogen resynthesis more efficient would be stimulated.

Javier Gonzales - 36:35: Exactly.

Dan Pardi - 36:36: That leads me then to morning exercise in a fast state. Do you get a different type of benefit by going right from the fasted period of sleep into doing some form of exercise without any food in your system? You're more likely to deplete your liver stores, could that be a beneficial driver to affect appetite regulation if some of these mechanisms are being challenged?

Javier Gonzales - 36:56: I think that probably depends on whether it's the rate of glycogen use or whether it's the total amount that is the major driver, because if it's the rate of use that is the big driver, then you probably do want to conduct the exercise in a fasted state and have less reliance on carbohydrate use, but you might achieve a lower absolute glycogen concentration. Whereas if you have a high-carb meal before exercise, you will stimulate glycogen use during exercise, but you might have more total glycogen available. So we can't be sure, but based on some of our work where we've manipulated breakfast and exercise timing, and sometimes we do that by completely skipping breakfast versus consuming breakfast, other times we just move that breakfast timing so people have it either before or after exercise, we do see some effects on appetite and energy intake.

37:46: If you skip breakfast, people don't seem to fully compensate for that later in the day, at least for up to 24 hours afterwards, so their total energy intake is lower. We've done a relatively short-term training study that isn't published yet, but it is pre-printed, which suggests that if you just manipulate the breakfast excise timing, so they're having the same breakfast every day it's just before or after exercise, that doesn't seem to influence energy balance so much. But the study wasn't designed to answer that question, so we probably need to do some more work on that.

Dan Pardi - 38:16: Speaking of future work, what are some of the hottest questions in your mind as good next steps to advance our understanding of the subject matter, given what we know?

Javier Gonzales - 38:26: For me, it would be the most important point is to determine, firstly, the main signal. So is it glycogen use or is it total concentration? And to do that, we probably need to combine some of these metabolic traces with direct measurements of liver glycogen with MRI technique. And then the second step is to understand the mechanistic link between carbohydrate use and/or content and appetite, whether that's a neural mechanism or whether it's a hormonal mechanism.

38:55: Some of the other interesting aspects that seem to respond to substrate metabolism are some of the appetite hormones, such as GLP-1, which seems to respond to fatty acid availability. So maybe performing exercise in a fasted versus fed state also influenced some of these other gut hormones and hormones that influence appetite.

Dan Pardi - 39:15: And possibly other interactions with other nutrients like leucine?

Javier Gonzales - 39:18: Definitely, so other dietary components, and perhaps manipulating timing and type of macronutrients in and around exercise sessions to minimize the compensation of energy intake post-exercise.

Dan Pardi - 39:31: I'm glad that you have taken up the torch here to take a field that had become dormant and say, Maybe we haven't completely exhausted our understanding here with the research that had been done, let's look more closely at differences between muscle and liver and timing and all that. Do you have any work coming out in the next couple of months?

Javier Gonzales - 39:47: Yeah, we have a study under review at the moment, which is a six-week exercise training study in the fasted versus fed state. Hopefully that will bring some light to the area. It's a topic that I'm really keen to do a lot of work on in the future, so there'll be plenty more, hopefully.