Nutrition is arguably the most emotionally charged of all of the applied sciences. If you have ever tried to discuss diet on the Internet, you know what I am talking about here.

Why is that? I can think of a couple reasons why it is so contentious.

For one thing, all of us eat, meaning that every single one of us is personally invested in this topic, and we interact with it all the time. We all develop a sense of expertise, in a way that we might not for something a bit more removed from our daily life, like robotics or civil engineering.

In addition, food is a primal motivator (arguably the most powerful that there is). Every single one of us has cultivated deep-seated dietary preferences, often established in our formative years. In other words, we are all biased, to varying degrees. It’s hard for us to view our favorite foods in an entirely objective way – even when they are slowly making us sick.

This, of course, is where nutrition science should save the day, right? The scientific method is designed to minimize the influence of bias and help us understand the natural world based on observable phenomena. But with modern nutrition, it’s never that simple.

 

FOOD IS NOT THE SAME AS DRUGS

Here’s part of the problem. As you probably know, when we study pharmaceutical interventions, we randomly assign participants to one of two groups: either the substance being tested or placebo (or usual standard of care in some cases). With this approach, we can be fairly confident that a statistically significant difference in outcomes is due to the experimental treatment, because the groups started out being otherwise similar. This is the gold standard, with good reason.

In theory, double-blind randomized controlled trials with hard clinical endpoints would also be ideal in nutrition science. But such trials are not feasible for addressing the major questions we have related to diet and health. There are obvious ethical and financial limitations, but also a plethora of serious issues connected to the behavioral component of diet.

Here’s just a few:

• Blinding is difficult (often wholly impossible) in dietary intervention trials.
• Dropout rates of dietary interventions are very high (trials to assess weight loss often have dropout rates of 30-40%). This causes all kinds of problems with data collection and interpretation.
• Compliance is notoriously low in nutrition interventions, often rendering the results meaningless.
• Finally, the clinical endpoints associated with diet and nutrition-related diseases like obesity or diabetes take a very long time to develop and require decades of follow up.

This makes nutrition science – and by extension, the science of obesity and metabolism – terribly complicated. Nutrition science must rely on a mixture of prospective cohort studies, mechanistic studies in humans, animal research, and randomized controlled trials assessing intermediate outcomes or surrogate markers. This demands careful interpretation of a very broad base of evidence, rather than relying on individual trials or single measures of association. Human nutrition is messy, and it’s easy to be led astray, or to gravitate to simple solutions to what is actually a very complex problem.

Our guest today knows that all too well.

 

GUEST

In this episode of humanOS, we welcome back Stephan Guyenet. Stephan spent 12 years at the University of Washington researching the neuroscience underlying body fat regulation. You can find more of his excellent work here. Pro users of humanOS will recognize Stephan from the Ideal Weight Program, on which we collaborated. Stephan is also the author of The Hungry Brain – Outsmarting the Instincts That Make Us Overeat.

Most recently, he’s launched RedPenReviews.org, a website where scientists utilize a standardized method to do thorough reviews of popular health-science books.

Stephan has inadvertently become a frequent guest to the show. Long-time listeners may recall previous conversations with Stephan, in which we talked about why we are fatter than our ancestors, whether high-protein diets are actually bad during weight loss, and the safety and effectiveness of ketogenic diets for treating type 2 diabetes.

Earlier this week (as of this writing), Stephan appeared together with journalist Gary Taubes on the Joe Rogan Experience podcast. If you haven’t watched that yet, please go ahead and tune in – it’s a bit long but thoroughly entertaining, perfect for an extended walk on the treadmill. Gary, of course, is best known as the author of the books Good Calories, Bad Calories, Why We Get Fat, and The Case Against Sugar.

This debate was meant to zero in on what causes obesity, and what causes insulin resistance (and the diseases associated with insulin resistance, such as diabetes).

Let’s quickly review these men’s perspectives, and where they disagree.

 

WEIGHTY ISSUES

Gary argues that obesity is a disorder of excess fat accumulation, rather than an outcome of energy balance. He believes that body fatness is dictated mainly by hormones that influence fat storage and fat utilization as fuel. The hormone insulin plays the biggest role in Gary’s model. Gary suggests that carbohydrates raise insulin levels, and elevated insulin effectively shuts down the use of fatty acids as fuel – meaning that you burn less fat and, presumably, become fatter. He also argues that carbohydrate consumption is the cause of insulin resistance.

Broadly speaking, Gary seems to think that both obesity and insulin resistance are relatively simple problems with a single unifying cause (carbohydrate content of the diet). Other factors that have been shown to play a role, like physical activity, caloric intake, and the lipid content of the diet, are not significant contributors in his model.

Stephan has a somewhat more complicated perspective on this. Stephan argues that the primary determinant of body fatness is the brain. The brain regulates appetite, cravings, activity, how much we eat, and other relevant aspects of physiology. We tend to gravitate to energy-dense foods, because such fare would have been associated with greater survival and reproductive success in challenging environments with variable food availability.

But wild animals often share these preferences, yet they seldom struggle with obesity – so why are we so different?

Our environment has changed. As Power and Schulkin aptly put it, in The Evolution of Obesity, “We evolved on the savannahs of Africa; we now live in Candyland.” We have constant access to calorie-dense, hyper-palatable food, which is usually high in both fat and carbohydrates. Incidentally, a doughnut is an excellent example: I know people tend to think of doughnuts as being a carby/sugary treat, but doughnuts are actually relatively high in fat as well. This combination is uncommon in natural foods, and we seem to find it fairly irresistible.

Worse still, we no longer have to engage in physical work to acquire these sorts of foods – in fact, our artificial world virtually discourages physical activity for most of us. Consequently, we are more likely to overeat (particularly if we are genetically susceptible), and we are less likely to expend enough energy to balance out these extra calories. In addition, once we’ve gained weight, alterations in brain circuits that regulate fat mass make it tough to take it off.

So, why have Stephan back on the show this time? Well, despite the duration of the debate (more than 2 and a half hours), a lot of juicy material relevant to this topic didn’t get addressed in the discussion. Prior to the debate, Stephan compiled and posted a list of scholarly references that he planned to draw upon (a handy resource that you should open, if you can, during the debate). But if you take a look, you’ll notice that there’s a good deal there that he didn’t get to. Accordingly, we thought it would be a good idea to have him on the podcast, to address important research that he didn’t get a chance to talk about in the debate, and clarify anything that he felt wasn’t fully elucidated in Tuesday’s discussion. Check out the interview to learn more!

 

LISTEN HERE

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YOUTUBE

TRANSCRIPT

Stephan Guyenet:	00:00:06	If people had actually followed the 1980 Dietary Guidelines in letter and spirit, which recommended unrefined foods, unrefined carbohydrates, less sugar, less added fats, I think we probably would be slimmer and healthier than we’re today.
Kendall Kendrick:	00:00:20	humanOS, learn, master, achieve.
Dan Pardi:	00:00:33	Hey. This is Dr. Dan Pardi and today is March 20th, and it is one day after Dr. Stephan Guyenet was on the Joe Rogan Experience podcast. The show was one of the largest podcast audiences in the world where he debated Gary Taubes, author of the books Good Calories, Bad Calories, Why We Get Fat and what to do about it, and most recently, The Case Against Sugar.
Dan Pardi:	00:00:56	Now Stephan and Gary have had a long-standing and public dispute, mostly revolved around the primary mechanisms driving fat gain, and in the Rogan interview yesterday, it was mentioned that the original spat between Stephan and Gary occurred at the first ever meeting of Ancestral Health Symposium that took place at UCLA in 2011. At that meeting, both Gary and Stephan presented but it was after Stephan’s talk that Gary came up to the mic and asked questions.
Dan Pardi:	00:01:21	And while that’s perfectly acceptable to challenge someone’s thinking or data of someone’s thought, Gary did so a bit in a rude manner, which he actually apologized for yesterday in the chat with Rogan, but this did seem to set the tone for the interaction between these two for years to come. Now, at that same meeting, Stephan and I met. We probably had close to two hours of discussion on the mechanisms involved in fat regulation with each other. We shared our own research in the subject and basically decided to keep the conversation going after the meeting ended.
Dan Pardi:	00:01:51	This eventually led to us working collaboratively on what we now have as the Ideal Weight Program, and now, today, our discussion is not going to be discussing that at all, but it is important to mention that relationship here. So, Stephan and I have not spoken since the Rogan interview. We don’t have planned agenda for this discussion rather we’ll just see where this conversation takes us as we reflect on yesterday’s show and I think it will make for an interesting discussion.
Dan Pardi:	00:02:15	So, today, Stephan, welcome to humanOS Radio and thanks for taking the time to join me.
Stephan Guyenet:	00:02:19	Yeah, thanks for having me, Dan. Good to be here. I wanted to really briefly address this interaction that Gary and I had at the Ancestral Health Symposium so many years ago. Gary, he is a little rough around the edges in the way that he communicates and he said something rude and he apologized for it, not that long afterwards. I accepted his apology. As far as I’m concerned, that is water under the bridge. That is gone and that does not bother me at all anymore and that’s not a driver of our interaction.
Stephan Guyenet:	00:02:51	The reason why I am prickly about Gary and of course, he’s prickly about me as well, is that he is perhaps the single largest source of public misinformation in my area of expertise. And so, perhaps someone who is consistently making these poorly supported assertions and thing extremely insulting things about your field, that is what annoys me and that is the reason I’m prickly about him, not because of something he said at a conference many years ago.
Dan Pardi:	00:03:26	What’s some valid points that Gary makes coming from his perspective?
Stephan Guyenet:	00:03:29	So, I think there are a couple of things. First of all, refined carbohydrate and sugar are fattening, in my opinion, and restricting carbohydrate is slimming. And as I said in the beginning of the debate, I’m not anti-low carb by any means. If anything, I’m pro low carb because I think that it is a valid tool among others for controlling body fatness and blood sugar levels. And as you know, in the Ideal Weight Program, both of our primary weight loss diets are carbohydrate reduced.
Stephan Guyenet:	00:04:00	And so that is a tool that I believe in and incorporate into our program to put my money where my mouth is on that. So yeah, so we agree there. And I would also say that very, very broadly, at the broadest level, I agree with Gary that there are problems with science and how science is done, and this is something that most scientists will agree with as well. We’re going through something right now called the reproducibility crisis or the replication crisis. We’re finding that a lot of the studies that we thought were reliable are actually not that reliable.
Stephan Guyenet:	00:04:36	When we try to replicate them in a rigorous way, we find that they’re not replicating as well as we could, and there’s this huge effort happening right now inside the scientific community to figure out what’s going on and correct that, and maybe we can talk about that later. So I agree with Gary that there’s a problem there, but the problem is that Gary is selectively skeptical about the evidence. So it’s not about applying overall rigor to the scientific literature, it’s about applying skepticism to findings that undermine your personal beliefs. That’s kind of the difference there.
Stephan Guyenet:	00:05:10	But the other thing that I’ll give Gary credit for, and this is something that I’ve said many times, I think the thing that is really the most positive thing that Gary has done is that he has given people permission to try a low carbohydrate diet because some of these messages were coming from the scientific community, the public health community, the medical community. They were hearing that these diets were … It’s going to kill you. It’s going to make your heart explode and you’re going to drop dead or whatever, and they were fearful and so they didn’t try it.
Stephan Guyenet:	00:05:42	And I think Gary’s book gave people permission to try it and this is the biggest point of feedback that I get from people when I get pushed back. When I critique Gary’s ideas, people say, “I tried low carb diet and it really helped me. I read his book and it really helped me.” And so I think that is another bright spot that we can talk about and that’s not what I object to. Clearly, I don’t object to the idea that refined carbohydrate is fattening or that even carbohydrate, in general, plays some role in obesity.
Stephan Guyenet:	00:06:16	I don’t object to the idea that restricting carbohydrate as a useful tool. What I object to is focusing the entire world around carbohydrate at the expense of these other factors that are also important like calorie intake and dietary fat intake and physical activity that Gary has argued, at length, are unimportant and that’s really where we diverged, is that I think that that is not only incorrect but dangerous.
Dan Pardi:	00:06:44	What is his model and then what is your model?
Stephan Guyenet:	00:06:47	Yeah, absolutely. So the first thing I want to say here is that Gary and I put together a document together that explains both of our models, and that document is published on my website, stephanguyenet.com or you can go to wholehealthsource.org. There’s a post there on my website, right now, it’s the first post, about the debate with Gary and I have all of the references listed out that I thought I might refer to during my debate and I was calling out numbers to those references during the debate.
Stephan Guyenet:	00:07:21	At the top of the page, I have a link to that document. It’s just a two page PDF. One page is just simple figures illustrating our models. And so if anybody wants to dig a little bit deeper and read and see for themselves, I think the figures are especially useful. Just click on that and download it and you can see it. I’m going to describe it here for folks who are not going to follow that link. I’ll just give a really brief overview.
Dan Pardi:	00:07:47	Perfect.
Stephan Guyenet:	00:07:48	The first sentence here that he wrote, “Obesity is a disorder of excess fat accumulation, not energy balance [how much we eat and expend]. So, essentially, he believes that that tissue is the core issue. The factors that are happening and acting on fat tissue is the core issue with obesity that some people have fat tissue that has a greater propensity to kind of suck up fat than other people, and that’s what causes people to fatten.
Stephan Guyenet:	00:08:20	And so, basically, when you are experiencing this fattening process of fat cells taking up too much fat and not releasing them enough, that is the cause of obesity and that also causes people to eat more and to feel tired and for their metabolic rate to go down. And so the excess calorie intake or increase in calorie intake and the reduction in physical activity, for example, are not causes of the obesity. Those are the result of the fattening process. So that’s what his model says. It’s a fat cell centric model.
Stephan Guyenet:	00:08:55	And my model, on the other hand, says fat cells are not the thing that regulates the size of fat cells. They’re more of a passive acceptor of the amount of energy that’s hanging out in your body and the brain is really what regulates body fatness. So the brain generates our hunger and our craving. It determines what and how much we eat, how much we move. It actually has circuits that actively regulate our body fat, just like the brain regulates body temperature and blood pressure, etc.
Stephan Guyenet:	00:09:27	And essentially, the brain regulates how much we eat and how much we expend, and that is the primary mechanism that determines how much fat is in our fat tissue. Okay, so I left a little something out of Gary’s model. So it’s a fat cell centric model and the primary thing that’s pushing fat into fat cells is insulin and carbohydrate is causing insulin to go up. So it’s carbohydrate leading to insulin, leading to fat cells, accumulating fat, which then leads to obesity and hunger and a reduction in metabolic rate.
Stephan Guyenet:	00:10:01	Now, my model says we have this food environment where we have all of these convenient calorie dense tasty foods rich in carbon fat. We are not moving our bodies very much and we have stress and sleep issues and all this, and those things interact with our ancient brain circuits that evolved for a very different world than we did and that causes us to over-consume calories and it causes the regulatory systems in our brain that regulate body fatness to regulate at a higher level.
Stephan Guyenet:	00:10:34	So kind of like turning the thermostat up from 60 to 70, your brain is regulating not around 170 but around 250 and so that then makes it really hard for you to lose weight. So that’s an overview of our models.
Dan Pardi:	00:10:51	A lot of the control of body fatness is an automatic or autonomic process, not entirely, but a lot of it. So like temperature or even blood pressure. We’re not consciously controlling this, but rather the brain is receiving signals from the body, responding to those signals and then trying to keep body fatness around a set point. Is this set point equally balanced on both sides of the seesaw, if you will? If you gain weight, will this mechanism drive weight down as powerfully as it will drive weight up if you’re losing fat?
Stephan Guyenet:	00:11:29	So, first of all, yeah, thank you for mentioning that. These are non-conscious systems. So that’s really important for people to understand is, I’m not saying that people who carry excess fat mass are deciding that they want to hold onto this fat or deciding that they want to consume more calories. These systems are operating in the background and beating us hunger and cravings and determining our metabolic rate. So these are non-conscious brain systems wearing along in the background. It’s not like any of this is conscious.
Stephan Guyenet:	00:12:02	So this question of whether the brain circuits that regulate body fatness are equally good at defending against weight gain and weight loss. It’s a really interesting question actually because it really depends on who you are. I think there are some people who actually are really good at not gaining weight, and we see this in controlled studies. If you overfeed people, you can feed people by thousands of extra calories, and some people just don’t put on very much fat. They just burn off the excess calories.
Stephan Guyenet:	00:12:41	They eat more and their brains, for whatever reason, just ramp up their metabolism and burn it off and we don’t really know how that happens. We don’t really have a very good mechanism figured out for exactly how that happens. And by the way, there are a lot of people too who don’t do that. So you overfeed them by the exact same number of calories and they’d take every excess calorie and pack it away into their fat tissue. Of course, those are the people who are more susceptible to weight gain, but there are a lot of different reasons why a person can be susceptible to weight gain.
Stephan Guyenet:	00:13:15	You could either be someone who’s appetite circuits are naturally regulated to a lower level and so you don’t eat very much, even though you would gain weight if you did. And then there are other people who have lots of appetite, but they’re wired so that even if they do overeat, they just burn it off. And so there are different ways that you can be lean depending on genetic roulette primarily.
Stephan Guyenet:	00:13:45	But what we see more reliably is on the other end that the brain doesn’t like people to lose fat that’s more consistent and we have a better idea of how that works. And you see pretty much the same thing in lean people and people with obesity, whatever someone’s current weight is, they’re just comfortably at if they’re just eating as much as they feel like eating. If you try to get them to lose weight, particularly by just straight up calorie restriction, portion control, what you see is a starvation response.
Stephan Guyenet:	00:14:18	So the brain detects that decline in body fat mass and we know that happens because leptin declines, that’s how the brain knows that fat went down and then it activates the sort of starvation response. It’s like you have your thermostat set to 70 and the temperature in your house goes down to 68. Well, suddenly, the heat’s going to come on, right? That’s basically what the body does, except it’s more complicated than just one thing. What you have is an activation of hunger. You have an activation of food reward circuits that generate cravings.
Stephan Guyenet:	00:14:53	You have an activation of circuits that make you more responsive of food use. There are studies, they put people in fMRI machine and they wash their brain circuits light up that have demonstrated this and then it also reduces your metabolic rate. The primary way in which it fights that loss is by trying to get you to eat more, but it also reduces the metabolic rate. And so all these things together, this is a coordinated response by the brain to try to get that fat back and it tends to be pretty effective.
Stephan Guyenet:	00:15:25	The reason is that when your non-conscious brain circuits are constantly pushing you with hunger and cravings and reducing your metabolic rate, etc., it’s really hard to resist that indefinitely and keep your calorie intake low or keep your physical activity level high. Essentially, one part of your brain, the conscious part that’s trying to make good decisions about your diet and lifestyle is fighting the non-conscious parts of your brain that don’t really care about any of that and they just want you to regain the fat. So that’s what you end up with and that’s why weight loss can be challenging. And often people regain.
Dan Pardi:	00:16:07	With weight gain, depending on the individual’s genetic composition, their experience of weight loss and weight gain in their life, what their lifestyle is like and their diet, etc. When somebody does gain weight and their set point is elevated, so let’s say somebody gains 50 pounds, they stay there for a while, then they lose 30. Even though there are still good 20 pounds of fat overweight, their body is responding as though they were a lean person who lost weight and they’re now starving and it tries to get their body fat level back up to 50 pounds overweight, and that’s one of the more frustrating things about weight loss. What are some of the mechanisms that are causing the elevation in set point?
Stephan Guyenet:	00:16:53	So this is something I’ve thought about a lot and I can’t give you a super competent answer on this because there’s still uncertainty in the scientific literature, but we do have some leads certainly. And one of the things that’s been shown pretty clearly to affect the set point in animal models, and there’s some evidence for this in humans as well, is the reward value of the diet. And so essentially, to unpack that a little bit, some food cause more dopamine release than others.
Stephan Guyenet:	00:17:22	We know that pizza is more seductive than celery sticks, and we know that ice cream is more seductive than plain lentils, and why is that? It’s because those foods have different physical and chemical properties that stimulate dopamine in the brain to different degrees, generating different levels of motivation. The things that stimulate dopamine are carbohydrate and fat and protein and salt and glutamate, which is that meaty umami flavor and up to a point, the higher the concentration of those things, the more dopamine you get.
Stephan Guyenet:	00:17:55	And especially when you start combining those things together, that’s when you really get these big dopamine spikes that are probably larger than what our ancestors used to experience with unrefined natural food. Our ancestors, they couldn’t just go to the grocery store and get ice cream or order a pizza. These would’ve been extravagant for the average person. And of course, there were wealthy people who could eat rich foods like those and they often developed obesity even in ancient times.
Stephan Guyenet:	00:18:24	And so what you see is that when the foods are more stimulating in this way, more seductive in animal models, they will tend to defend a higher level of body weights. They will develop obesity and then you can perturb their weight by restricting their calorie intake on the same diet a bit, and you will see that they will bounce right back up as soon as you let them eat more of that diet again. So that shows that they’re not just passively at that weight, they’re actually actively defending that higher weight.
Stephan Guyenet:	00:18:56	So you can perturb the weight and it will bounce back to where it was. That’s how you know that it’s actually being regulated and it’s not just a passive thing. And there are signs that this happens in humans as well. So, basically, the way I think about it, this is just my way of conceptualizing it. There’s not really any way to directly test this, but the way I think about it is that the brain is basically saying, “This is a very preferred food. This is something that’s really pushing my buttons and I love it. So I’m going to find ways to let you eat more of it.”
Stephan Guyenet:	00:19:29	And so it increases that point so you can eat more of the highly preferred food and it also will shut down satiety mechanisms, that’s another thing you see with more highly palatable foods that they’re not a filling. Basically, the brain seems to find ways to get more of it into your body when you are eating these foods that on an intuitive instinctive level, the brain finds highly seductive.
Stephan Guyenet:	00:19:55	That’s one way. But I just want to quickly get through the other thing cause I think it’s really a convergence of factors that’s happening. So I think that’s the one thing. One of the things that’s been shown in rodents at least, this haven’t been demonstrated in humans yet. But in rodents, the increase in leptin itself seems to be required for leptin resistance to occur. And I guess I glossed over this, but leptin resistance is the cause of the increase in set point.
Stephan Guyenet:	00:20:26	The resistance to the Hormone Leptin that tells the brain how much fat you have on your body and that seems to be caused by high levels of leptin itself or at least that is required for it to occur. And so how do you get high levels of leptin? Well, there’s basically two ways. One is you have higher fat mass that’s kind of circular. The second way is you eat too much. So after Thanksgiving, if you consumed more calories than you habitually consume, even though your fat mass hasn’t changed much, you see a spike in leptin.
Stephan Guyenet:	00:21:00	And so I think that at least a plausible hypothesis is that we get these spikes in leptin and they gradually kind of be sensitize us to leptin and cause our set point to creep up and up and up and up a little bit more each year and each holiday season, for example. And that combined with some aspect of food quality that may be causing some inflammation in the hypothalamus that generates the set point. And that basically these factors together plausibly could account for it.
Dan Pardi:	00:21:31	If we think about a natural environment, the types of foods that are available and then the types of foods that are available now, the industrial food system engineers these foods that we love that tastes good and that are easy to overeat in.
Dan Pardi:	00:21:47	A talk that I gave a few years ago about why we get fat, I talked about how the nature of modern processed foods cause you to eat more calories before you’re full, which means that the sensory properties of those foods have less satiety factors. So they’re easier to overeat before you even have that sense of fullness and easier to eat after you’re full. The experience of you’re full after a meal, the dessert cart comes by and you’re offered something that tastes delicious.
Dan Pardi:	00:22:14	You’re not hungry, but you have in a renewed hunger for the pleasure that comes with those types of foods. It doesn’t necessarily mean now you’re a glutton. You don’t care about your health, which is really offensive to people to position it that way. We have a physiology that has been displaced in this unnatural environment and we’re acting naturally within this environment in every topic.
Stephan Guyenet:	00:22:33	Yeah, I think that’s a great way to frame it. These circuits in our brains are doing exactly what they evolve to do. These are the circuits that promoted the survival and reproduction of our ancestors. These circuits that drive us to really crave calorie dense highly palatable foods and make it difficult for us to restrain our eating behavior once we start eating those things and these circuits that make them less filling than other foods.
Stephan Guyenet:	00:23:01	These are all circuits that promoted the survival and reproduction of our ancestors because they drove our ancestors toward calorie dense nutritious foods that were going to support them, allow them to survive and reproduce in a difficult environment. And so there’s reasons why all these things like this and there are reasons why they push us in the direction that they push us, and you can’t feel guilty for the impulses you have. You can’t control your impulses.
Stephan Guyenet:	00:23:27	All you can do is control your behavior, but even that is limited. You can’t fight yourself all the time when you have these impulses bubbling up. Yeah, I think that’s absolutely right and I also want to say, I liked the way you framed it of these foods, they cause you to eat more before you’re full and then also more after you’re full, and that’s basically two different things happening in the brain.
Stephan Guyenet:	00:23:51	The causing you to eat more before you’re full is because of these foods do not triggers a satiety circuits in the brain as effectively per calorie. Just because of their physical and chemical properties, they’re very dense in calories, so they don’t feel your stomach as much per calorie and they tend to be lower in protein and higher in palatability, which also reduces how filling they are per calorie. And so you might have to eat twice as many calories of something like pizza to feel satisfied than you would from a plain baked potato and a piece of fish and some vegetables.
Stephan Guyenet:	00:24:31	You’d probably have to eat twice as many calories than the pizza before your brain tells you, “Okay, you’ve had enough.” And then the second part of that is these things push us to eat too much after we’re already full or essentially, another way of putting that is that there is a motivational drive that is independent of our hunger and I think that that’s really important to understand.
Stephan Guyenet:	00:24:54	The example you gave is a perfect one of why do you eat dessert after a meal? You’re not hungry anymore at the end of the meal, so why are you going to eat ice cream and why are you going to eat a brownie? Well, a big part of the explanation is because you have this dopamine driven, motivational urge, this craving to consume those foods whether you’re hungry or not. And the same way for beer, we don’t drink beer because we’re hungry for the calories. We don’t drink soda because we’re hungry for the calories. These things have a motivational valence that is independent of our hunger and independent of our body’s state of energy status.
Dan Pardi:	00:25:34	If you have a highly process purified high flour based diet, it’s not going to be eliciting the same satiety signals. One example of that is your gut microbiota. When you have fiber butyrate-producing bacteria, butyrate is a short chain fatty acid, will then stimulate something called GLP-1 which is a society hormone, and so you activate the satiety center. So bloodborne factors and also through the vagus nerve that then we’ll tell you, “Hey, I’m full here.”
Dan Pardi:	00:26:03	Imagine if the quality of your diet always meant that you were taking in 150 calories more, and I’ll use that number arbitrarily, every time you ate before you felt full. In the long term, how does the repeated consumption of these types of foods rewire and manipulate reward-driven eating so that the craving that occurs is driving eating in the absence of hunger? Both of those experiences give us insight into how the brain is being manipulated by the food environment, but is also then controlling the over-consumption of calories.
Stephan Guyenet:	00:26:36	I have the same experience with alcohol myself. So I find that if I consume alcohol every night, I really crave it on nights that I don’t have it and I really don’t want to have that kind of relationship with alcohol where it’s like my nights not complete unless I have some. And so I have this informal rule where I will only drink alcohol every other night, and by the way, I don’t drink a lot. I’m talking about like one drink or half a drink every other day. So it’s not talking about getting smashed.
Stephan Guyenet:	00:27:08	And that really helps break it up such that I just don’t have those cravings because I’m not consistently reinforcing my brain like that. And of course, alcohol is a little bit different to drug, however, the mechanism is the same. Alcohol increases dopamine release, these foods increase dopamine released, and so it’s actually pretty analogous.
Stephan Guyenet:	00:27:28	One thing I wanted to touch on that you mentioned, you mentioned flour-based foods and I think this is a really interesting topic because I think flour is kind of an insidious thing in our diets. It’s the thing that is perceived as kind of fairly healthy, especially if it’s whole grain is perceived as healthy and slimming. However, I think personally that flours are one of the more fattening things in the modern diet and wholegrain is definitely better, but it’s not all the way to where some people are going to need if they want to optimize their weight control.
Stephan Guyenet:	00:28:08	And the reason is, if you look at flour-based foods, most flour-based foods, it doesn’t apply to 100%, but most flour-based foods and particularly bread and baked goods, they’re calorie dense. They’re very calorie dense and they’re quite palatable, and people understand this is obvious for brownies and cookies and that sort of thing. Everybody understands that, but for bread as well. Bread itself is actually quite calorie dense because it doesn’t contain a lot of water.
Stephan Guyenet:	00:28:38	Especially after you toast it, there’s not a lot of water and so it’s calorie dense. It’s not going to have the same level of satiety. It’s not going to create the same level of satiety as like something less calorie dense like a potato and it’s pretty darn palatable. I mean, if you toast a piece of bread and first of all, generally you’re not going to eat it by itself. You’re going to make a sandwich out of it or you’re going to put butter and jam on it or you’re going to do something with it.
Stephan Guyenet:	00:29:08	And at that point, you’ve created something and it’s actually pretty palatable. I think bread is actually fairly insidious and flour-based foods, in general, are fairly insidious and that is why I recommend not eating those on the simple food diet that we created and also, obviously, on the flash diet.
Dan Pardi:	00:29:30	Flour-based products are something that will promote weight gain clearly for me. What do you think about the flour-based products that are gluten-free? There’s a huge assortment of them now. I know it’s hard to make one qualifying statement about all of them, but does simply removing the gluten remove the problem in terms of weight regulation?
Stephan Guyenet:	00:29:52	I don’t think so. Here’s the thing, I continue to have an open mind about gluten maybe being problematic in certain people or in certain scenarios. However, the evidence, we’re really hasn’t been that strong on that and the further we go along and the more it gets tested, the less convinced I am that it’s really an important factor. Again, I have an open mind about it, but the evidence so far just hasn’t really convinced me.
Stephan Guyenet:	00:30:19	And we have these really simple food properties like calorie density and palatability that readily explain why bread would be fattening and not filling, and those booed properties apply equally to gluten-free and to gluten-containing foods. And so, to me, I don’t really see much difference. Maybe there is a difference in the sense that gluten-free bread doesn’t tend to taste very good.
Dan Pardi:	00:30:44	They’re getting better.
Stephan Guyenet:	00:30:44	And so maybe it’s less fattening in that way but I don’t think it’s really that different and I think I’m tempted to call it health washing, although I’ve realized that for some people, people who have celiac disease, I realized that it’s actually really important.
Dan Pardi:	00:31:01	You mentioned brownies, delicious, most people love them. If you were to create a low-fat version, they’d be less palatable. Whenever you create the lower calorie version of something, it can look the same. They can add a lot of food science so that it has the same amount of creaminess, etc. A lot of times people will not continue to buy them.
Stephan Guyenet:	00:31:21	It doesn’t have that staying power. It doesn’t have the dopamine and it’s not hard to imagine why. I mean, all we have to do is imagine, think about a bowl of ice cream, your favorite flavor right in front of you, regular full fat ice cream and now think about that same ice cream completely fat-free. This is sweet but that free, it’s really not nearly as appealing. And then think about it sugar-free, not sweet at all, but just fat, that’s also not that appealing.
Stephan Guyenet:	00:31:49	Both of those, yeah, you’d probably eat some, they’d probably paved all right, but it does not have that same pull over you as the full thing where you have the carbs and the fat together. That is by far more delicious and more motivating, more seductive for our brain.
Dan Pardi:	00:32:07	If you don’t mind, I’d like to circle back a bit to Taubes’s argument about sugars and insulin. He paints them as the single source of the problem. Where do you see carbs and insulin fitting into your model overall?
Stephan Guyenet:	00:32:22	So I absolutely believe that carbohydrate is fattening, particularly refined carbohydrate including sugar. So white sugar I think is a factor that contributes to obesity. I don’t think that those things contribute to obesity via insulin, and there are a couple of reasons why I think that. The underlying physiology, despite what Gary says, does not point to higher insulin diet being more fattening. Because if you eat a higher insulin stimulating diet, yeah you get more insulin and yeah that releases less fat from your fat cells, but you’re also eating less fat.
Stephan Guyenet:	00:33:02	So you’re burning less fat, you’re eating less fat and you end up in the same place as if you’re eating a lot of fat and burning a lot of fat. So that doesn’t really tell us anything about which diets are more fattening based on insulin. But the other thing is that when you do controlled feeding studies, when you feed people equal amount of calories of carbohydrate and fat, you see changes in fat mass that are almost identical. And we have metanalyses of metabolic ward studies that had been done on this, 20 different studies, we’ve put them together and there’s almost no effect of varying the amount of carbohydrate and the amount of fat, which obviously varies the amount of insulin as well.
Stephan Guyenet:	00:33:46	And so this idea that insulin is like the gatekeeper or at least an important factor in what is going on in fat cells is just not true. Insulin, it does have important effects on the dynamic regulation of fat trafficking in fat cells that allows you to burn whatever you ate. So, again, you’re eating a higher fat, low carbohydrate diet, it allows you to burn that fat. You’re eating a high carbohydrate, low-fat diet, it allows you to burn that carbohydrate.
Stephan Guyenet:	00:34:23	So there’s this dynamic regulation that’s happening around mealtimes, but there’s not this kind of overall fat storage effect that’s really not implied by the endocrinology or the physiology of insulin, which is a kind of like one of the central argument with this idea. And this is why, when you look at Gary likes to cite textbooks a lot, and the textbooks talk about these effects of insulin on that fell enzymes that relate to that going in and out, and then he will pivot to that causing obesity.
Stephan Guyenet:	00:34:57	But if you read the textbooks, they never say anything about the regulation of the total size a body fat stores. Never say anything about fat accumulation, which is the word that Gary uses. What they talk about is the dynamic regulation process and one does not imply the other. That’s what’s really key to understand. So basically is carbohydrates, does that contributing to the problem? Yeah, sure. Absolutely. Is it via insulin? I don’t think so. I don’t think the evidence suggested it is.
Stephan Guyenet:	00:35:31	And there’s a lot of reasons why that is, but one of them is … So, according to Gary’s perspective, things that don’t release insulin are not fattening. So dietary fat, for example. Well, it turns out dietary fat is battening across a wide range of non-human species. And so if you just add that to the food of a rat or a mouse or a monkey or a pig or a dog or a cat, they will get fatter. It doesn’t add up.
Stephan Guyenet:	00:35:58	And you see the same thing in humans and we’re not fundamentally different from all of these other animals, but just in case anyone might think we are, you see the same thing and human randomized controlled trials. When you add that to people’s food, they eat more and they start gaining fat. And furthermore, there’s a drug called Orlistat that specifically inhibits dietary fat absorption in the gut. It causes you to not absorb about 30% of the dietary fat that you eat.
Stephan Guyenet:	00:36:27	And there are two-year long placebo-controlled randomized controlled trials, which is the highest level of evidence available showing that that drug causes weight loss, and so to say dietary fat is irrelevant, is simply incorrect. And by the way, Orlistat is not a silver bullet, not a great weight loss drug, but it’s only reducing dietary fat intake by 30%. You’re still absorbing 70% of the fat. So when you make a modest change, you see a modest effect. So that’s not surprising to me that it doesn’t do a lot.
Stephan Guyenet:	00:37:04	It would be like having a low carb diet study where you only reduce carb intake by 30%, I don’t think anybody would think that that would cause a whole lot of weight loss, but it demonstrates the principle of it. Why is it then that carbohydrate is fattening and why are low carb diets slimming and why are low-fat diets also slimming? Because you see actually very similar effect on both ends of the spectrum when people greatly reduced carbohydrate or if they greatly reduced fat, what you see as a spontaneous decline in calorie intake.
Stephan Guyenet:	00:37:37	Even people who are just eating to fullness, they will start eating fewer calories and they will start losing weight. You see this on both ends of the spectrum and it may not be exactly equal. I think it’s not exactly ironclad, but there’s at least some evidence that decline be greater on a low carbohydrate diet, but essentially, my way of thinking about this is that carbohydrate and fat are two of the primary things that cause dopamine to be released in your brain. So those are two of the most motivating seductive substances in the food that we eat and especially when they’re combined.
Stephan Guyenet:	00:38:14	Now if you get rid of the carbohydrate and you eat more fat, even if you replace that with more fat, that’s not as seductive for your brain. You’re not getting as much dopamine release and you’re not going to have the same kind of eating drive as if you were eating carbohydrate and fat, and same thing on the other end of the spectrum. That I think is a hypothesis that at least can explain the evidence on both ends of the spectrum. Whereas the insulin hypothesis, at least as articulated by Gary, can’t do that.
Stephan Guyenet:	00:38:45	There is one additional detail I’ll put in here just to be complete. The truth is if you really want to look at the actual evidence, dietary fat does increase in insulin levels and low-fat diet can reduce at least fasting insulin levels and so it’s a lot more complicated than the advocates of this hypothesis will be willing to discuss, but dietary fat intake, it may not increase your insulin levels very much acutely like right after the meal. It does increase them some but not a lot acutely.
Stephan Guyenet:	00:39:21	However, if you’re eating a diet that is very fatty and you’re over-consuming, that will increase your insulin level. That will increase your fasting level of insulin and the amount of insulin your body has to secrete to cover your blood sugar after meals. So, actually, it does affect your insulin and on a low-fat diet, if you’re eating fewer calories than you’re losing weight, your insulin will go down as a result of that.
Stephan Guyenet:	00:39:48	It’s a really complicated picture, the closer you look at it, but I haven’t seen any real evidence that insulin level is actually itself driving changes in body fatness and the general population. When Gary and I discussed this, I kept asking him for evidence and he wasn’t able to provide any. It’s the story that he tells that he does not have any real evidence to provide for it.
Stephan Guyenet:	00:40:15	There’s one piece of evidence that I think is really key here that I didn’t cite yesterday. I wasn’t able to get around to it, but it’s a really simple observation that people with higher insulin levels do not gain more weight than people with low insulin level. You cannot predict how much weight a person is going to gain by measuring their insulin. This has been studied many times and there have been dozens of studies on this because insulin and weight gain are two things that are very commonly measured in studies.
Stephan Guyenet:	00:40:48	And when you look at the literature as a whole, now you can cherry-pick any individual study and support any position you want, including that insulin is slimming. But if you look at the overall literature, there’s just no reliable correlation. Some studies say insulin is correlated with weight gain. Some say it’s correlated with less weight gain. Most of them say it’s not correlated at all. There’s no picture that emerges from the literature that says that higher insulin reliably predict greater weight gain, which just to be clear, if you believe that insulin is the primary driver of fat gain, you have to see a correlation. If there’s no correlation, that hypothesis cannot be correct.
Dan Pardi:	00:41:35	You two have been debating for quite a long time now, and in that time, I think it’s 13,000, 15,000 new references related to obesity every year. So the amount of data that’s coming out on some aspect related to obesity, there’s just a ton of research. It’s hard to keep up with it. Have you seen Gary update his perspective on things in the face of new evidence? And I’ll ask you the same question, how has your perspective at least evolved over the last 5 to 7 years?
Stephan Guyenet:	00:42:06	My perception has always been that Gary’s beliefs are completely resistant to any kind of update as a result of evidence. I have never seen Gary significantly change any of his views in respond to the evidence. And if you look at the evidence he cites, it’s generally stuff that happened 50 to 100 years ago. His idols are these pre-World War II researchers in Germany and Austria who were basically sitting around speculating about what caused the obesity with almost no data to back it up. And that’s like these are the guys who he thinks had the best idea of what causes obesity.
Stephan Guyenet:	00:42:49	And so all of the research that has happened, like the discovery of leptin, understanding of all these brain circuits that regulate eating behavior and all that, none of that stuff appears in his writing. It does not seem to inform his belief system. So I haven’t seen Gary update his beliefs at all, ever. As far as me, yeah, I’ve updated my beliefs quite a bit, especially writing my book where I talked to 36 different researchers. I learned a tremendous amount.
Stephan Guyenet:	00:43:19	And one of the things that has been really cool for me is learning more about the genetics of obesity. We, fortunately, got to focus on this quite a bit in our conversation yesterday, Gary and I. One of the things he got on my case about was I was saying that the genes that we have identified that tell us why some people are fatter than others, genetically, is that I was saying that we had identified 10% of the variance, whereas my book said, I forget, 2% or 3%.
Dan Pardi:	00:43:50	Yeah, 3% I think.
Stephan Guyenet:	00:43:51	Okay. Yeah, and he was getting on my case about that. I was like, “Gary, that was three years ago, man. This science is rolling. It is 10% now. That’s what happened in the last 3 years. This science is advancing very quickly.” That’s one of the areas that I think has been really cool for me, is being how that science is developing not only the science of obesity genetics but the science of insulin resistance and diabetes genetics.
Stephan Guyenet:	00:44:17	And essentially, there are different ways to look at the genetics of obesity. There are some ways that measure the whole contribution of genetics to obesity and then there are other ways that identify the specific genes that underlie it and those ways only identify a small fraction of the effect right now. And the reason is that you need so many people to do these studies. We’re up to 700,000 now, you need millions of people to capture maybe even half of the total genetic contribution.
Stephan Guyenet:	00:44:51	And so these studies, right now, are only capturing a fraction of the total of what we know contributes to differences in body fatness. And so to understand the total contribution of genes, you have to look at twin studies and family’s ideas and adoption studies, and what do these studies have shown is that about 75% of the differences in body fatness between individuals are attributable to genetics. And now these other studies where the smaller percentages come from, where they’re identifying the specific genes that underlie that, those as of right now have explained something roughly like 10%.
Stephan Guyenet:	00:45:30	What I mean by that, 10% of the differences between body fatness between individuals. So Sam is 150 pounds and Joe is 50 pounds, and maybe 5 of that can be explained by specific genes that we have identified right now. So that’s a rough way to think about it. But the cool thing is, you can look at these genes that we’ve identified and those tell you what the biological mechanisms are that underlie differences in body fatness and the genes that we have discovered first in these studies, even though we’ve only discovered a small fraction of them, the ones that turn up first are the ones with the largest effect size.
Stephan Guyenet:	00:46:12	And so that is what’s really important is all these genes that are turning up with the largest effect size are all about the brain. And so we have now 700 genes or is it 700? Maybe it’s 70 genes, I forget, 70 or 700? I forget off the top of my head, but it’s a lot of genes that we’ve identified that impact whether someone is fatter or slimmer, and there’s many more to be discovered. Each one only has a tiny effect individually.
Stephan Guyenet:	00:46:40	And at this point, if you measure 70 genes and you see that 40 or 50 of them are all about the brain, the probability that once you measure the next 70 that suddenly none of those would be about the brain is very low. We have enough of a sample size to know that differences in body fatness are very importantly regulated to the brain. It’s very unlikely that that’s going to change with additional information.
Dan Pardi:	00:47:09	Right. So the ones that pop up first in these studies are pointing to the brain where the source of the issue is?
Stephan Guyenet:	00:47:18	Yeah, and these genes have been identified precisely because they are the most influential.
Dan Pardi:	00:47:24	If Gary’s model was correct, you would see these relating to enzymes and hormones related to the shuttling of triglycerides and fatty acids in and out of the fat cell.
Stephan Guyenet:	00:47:36	Absolutely, and what we see is that there are tons of genes that could have come up in these analyses that do come up when we’re looking at other types of traits like body fat distribution, but not how much fat you have, but where that fat is. We do see a lot of fat cell in until unrelated genes there in type 2 diabetes genes are all about insulin. So these genes are there. This genetic variation is there. If it was important for obesity, it would be popping up in these studies but at least it’s not popping up as the primary contributor.
Stephan Guyenet:	00:48:10	I should add that, I don’t want to give you the impression that every single one of these genes it’s popping up is about the brain. There’s probably a lot of things that are involved to some extent. However, when you look at the big picture of new things that are popping up, what you see is that they are dominated by brain-related genes. That is the single largest contribution.
Dan Pardi:	00:48:31	Gary talked a bit about this phase lock idea, how we’re locked in our own narrative. We can’t think outside of it and therefore, we’re only perpetuating research that is under these concepts that we think are true but clearly aren’t.
Stephan Guyenet:	00:48:47	Essentially, he thinks that we get some idea in our heads as researchers that usually comes from nowhere and we stick to it and can’t think outside the box anymore, like the guy looking under the lamppost for his keys because that’s where the light is even those keys are somewhere else. So that’s his framing of it, but what I find is … And this has been narrative, this is part of his whole story about how science works and how it got everything wrong about obesity.
Stephan Guyenet:	00:49:20	But what I find is that when Gary states that scientist assumed this or assumed that because they were blinkered because they were in this phase lock, generally, there are actually reasons that scientists believe those things. There’s actually evidence for that, that he’s just not sharing with you. He either is not aware of it or chose not to communicate it to the audience.
Stephan Guyenet:	00:49:46	And a great example of this was in our debate when he was claiming that the hormone leptin was having most of its effect, not in the brain but outside of the brain, below the neck as he said. He was saying that researchers such as myself are so phase locked on this idea that leptin acts in the brain that we wouldn’t even consider that it would act outside of the brain, and this is just like …
Stephan Guyenet:	00:50:11	The things that he says confidently are so extraordinary because in my lab, my mentor’s lab, Mike Schwartz, we were constantly testing whether things were working inside or outside of the brain. That was one of the main things we did in our lab and so it just like completely made up, but it fits the narrative that we are the use automatons that can’t see outside of our own basic ideas. But yeah, he was saying that leptin actually, maybe it’s acting in the body. Well, it turns out that that idea has been tested extensively already and he’s just not aware of the research.
Stephan Guyenet:	00:50:48	So there’s research where we knocked leptin receptors. I say we, I was not personally involved in the research, knocked it out of the brain, knocked it out of the hypothalamus where it mostly acts, knocked it out of specific populations of neurons. Guess what? You completely replicate the obesity when you just knock it out of neurons. So you get animals that are just as fat when the brain can’t hear leptin as you get when in animals that can’t hear leptin at all anywhere.
Stephan Guyenet:	00:51:18	And so it’s not that we have assumed this because we’re in some kind of phase lock, we have determined that this is true because of extensive evidence and not scientific hypothesis testing. This is one of the places where I really object to Gary as narratives to see this is a really recurring theme to him at scientists just assumed this or they assumed that and they weren’t thinking about this alternative hypothesis when in many cases, and I would say most cases, actually there was evidence to support their beliefs and maybe they did consider the alternative hypothesis and they rejected it.
Stephan Guyenet:	00:51:58	Gary will say that we need to keep all hypotheses in mind. We need to keep his hypothesis in mind, but no, we don’t. At some point, when hypothesis has been rejected sufficiently, you don’t need to keep it in mind anymore. You don’t need to keep testing it. It’s done. It’s over. It’s dead and buried. You move on to different hypotheses. You don’t keep banging your head against the wall once you’ve already demonstrated that something is wrong.
Dan Pardi:	00:52:23	Most scientists that are working in the space care deeply about finding good solutions and what would you do as a scientist? You go where the evidence takes you and you’d then say, “How do we advance our understanding and a meaningful way?” Now that doesn’t mean that there’s not problems in science, but he plays this narrative of, “If the scientists had gotten it right, we wouldn’t be in the problem that we’re in. We’re in this pickle because they’re fumbling and bumbling around, and it’s not like the government has come out with these policies and people have been following to the letter and look at the pickle that we’re in now.” That’s not how this works, but that’s how he paints it to work, which is seductive.
Stephan Guyenet:	00:52:56	Yeah, absolutely. It’s very seductive, especially in the United States, this is a narrative that goes back hundreds of years. This is part of our culture to blame the government for things and to blame authority structures for things, and this is part of a cultural phenomenon that gives buoyancy to these types of ideas.
Stephan Guyenet:	00:53:16	But if you go back to the 1980 Dietary Guidelines and you actually look at what they said, one of the points of emphasis was to eat less sugar. And if people had actually followed the 1980 Dietary Guidelines in letter and spirit, which recommended unrefined foods unrefined carbohydrate, less sugar, less added fats, I think we probably would be slimmer and healthier than we are today. And then you see when you put people on this type of a diet, like in the diet fits study that Brian Gardner did, they lose weight and they get healthier even if you don’t give him any specific calorie target.
Stephan Guyenet:	00:53:53	Now is that the optimal diet for everyone? Probably not. And is that the optimal diet that you should be giving as public health advice? I really don’t know the answer to that. But is it better than the diet that we typically habitually eat? Yeah, it definitely is. And so to blame it on that, it’s a weak argument.
Stephan Guyenet:	00:54:16	I will say this, there is a point that I think is valid that people have made and that is that, “Okay. The guidelines weren’t necessarily that bad, at least the early guidelines were not necessarily that bad, but the way that the food industry responded to those guidelines and the way that government and the food industry and organizations like the American Heart Association interacted around those guidelines was not good.
Stephan Guyenet:	00:54:43	I forget who pointed this out to meet. Somebody sent me this on Twitter and I think I maybe it was vaguely aware of this when I was a kid, but I had forgotten about it. The American Heart Association would put its seal of approval on certain types of foods that met its guidelines. And somebody sent me a photo of this horrible sugary candy cereal. I forget what cereal it was, but it was just like one of these really bad sugary things and there was the American Heart Association seal of approval.
Stephan Guyenet:	00:55:17	I don’t want to say that there’s not any kind of fruit that there might’ve been something there, but I think the narrative is really exaggerated. And furthermore, I would say that for someone who prides himself on being very skeptical of using observational evidence and correlations to make his points, he sure seems decided a lot and rely on it a lot.
Dan Pardi:	00:55:39	Every type of study has its limitations and it doesn’t mean that they’re not helpful to furthering our understanding.
Stephan Guyenet:	00:55:45	Yeah, absolutely. I think you do have to look broadly at the literature and you have to try to draw your information from many different sources and I actually think that this is one area where my background is kind of complementary to. A lot of the people that I interact with in the health and nutrition environment is that I have this background in the animal literature and I think that that is quite complimentary, not in the sense that just because something demonstrated in animals doesn’t necessarily mean that it’s definitively demonstrated in humans.
Stephan Guyenet:	00:56:20	However, it is a piece of evidence that we can consider because as you said, all types of evidence have limitations and so you do a randomized controlled trial and maybe there’s not enough time to see how a specific disease is developing or you’re measuring something that may or may not be correlated with the thing that you’re interested in. Whereas in animal models, you can completely control an animal’s diet and environment for its entire life with no error, and that’s huge.
Stephan Guyenet:	00:56:48	You have a level of control that is far beyond what you can get typically under human scenario. That doesn’t mean they’re better studies. It just means that it’s a different type of information that can be integrated to come to better conclusions. For example, with the ketogenic diet, one of the things that has made me more comfortable with it and more favorable toward it, just recently in the last year or two, is these findings in rodents where you put animals on a ketogenic diet and they’ve stayed slimmer for their entire lives and they’re not really having any health consequences and they live either the same length as normal mice or they maybe even live a little bit longer.
Stephan Guyenet:	00:57:32	That, to me, is a piece of evidence that makes me more comfortable that this diet is not going to have some unforeseen horrible consequences down the line that we aren’t anticipating because all we have is short-term data. So it doesn’t prove anything definitively, maybe there could be issues in humans. For example, rodents are not susceptible to human types cardiovascular disease. They don’t develop coronary artery disease and so that’s kind of a question mark, but it is a piece of evidence that has contributed to me feeling more comfortable. So that’s just an example.
Stephan Guyenet:	00:58:09	Anyway, I’m just ripping off what you said, but one last point I’ll make is that even though we should be looking broadly across different types of evidence and we should be integrating them into our decision-making process, I think it is important to recognize that not all types of evidence are equal. There’s some types of evidence that are more informative than others or that can better support causal inference. In other words, give you a better idea of what’s happening in cause-effect relationships and go beyond just association.
Stephan Guyenet:	00:58:45	And so, for example, I think a lot of people have been critical of nutritional epidemiology where we’re striving diet-disease correlations in big populations and I think rightfully so. I hesitate to say that those studies are not useful at all, but I think it’s very difficult for me to know how useful they are. It’s very difficult for me to evaluate how informative those studies are and so it’s kind of a question mark for me.
Stephan Guyenet:	00:59:16	And there are certainly some instances in which they have gotten things very, very wrong. We also shouldn’t this false equivalents attitude where all types of evidence are equal. We have to recognize that, for example, if you have a multi-year large well-conducted randomized controlled trial with actual disease outcomes, such as we have many of these for type two diabetes, then that’s gold standard. Like if you have an animal study that contradicts that, you’re not going to pay attention to the animal study. You’re going to say the animal study got it wrong because we have this much more definitive piece of evidence.
Dan Pardi:	00:59:53	We have a lot of types of evidence that will further advance our hypotheses that are then better tested in the gold standard manner, yet altogether, they paint a clearer picture than they do individually, but they shouldn’t all be weighed equally.
Stephan Guyenet:	01:00:08	Yeah, absolutely.
Dan Pardi:	01:00:10	You recently launched Red Pen Reviews. People are really excited about this effort. First, tell us about what it is and then about your method by which you are evaluating the books.
Stephan Guyenet:	01:00:23	So our goal with Red Pen Reviews is to provide the most informative, consistent, and unbiased health and nutrition book reviews available. So we’re reviewing popular health and nutrition books that are targeted toward a fairly general audience and that people are hearing about, they’re reading, their doctors and nutritionists are hearing about and are interested in. And we’re trying to give people tools to understand whether those books are evidence-based and helpful.
Stephan Guyenet:	01:00:54	So whether they should read those books, whether those books are going to benefit them and at the heart of what we do is the Red Pen Reviews method. And so it is a semi-quantitative expert review method that scores books. It gives them numerical scores on scientific accuracy, reference accuracy and healthfulness, and what semi-quantitative means, basically, that we have a scoring rubric that assigns numbers to different levels of things.
Stephan Guyenet:	01:01:29	And so when we’re evaluating a particular reference, we’ll say like, “Does this evidence support the claim strongly? Does it support it weekly? Does it support it not at all? Does it contradict the claim?” And those each have numbers and so that’s how we developed this semi-quantitative scoring system. We don’t call it quantitative because quantitative would be like measuring the book with a ruler. That’s not really what we’re doing. It’s not completely objective.
Stephan Guyenet:	01:02:00	However, semi-quantitative is assigning numbers based to our judgment. And the cool thing about that, the really cool thing about that is it allows you to get this really concise summary of the book. So you can land on the landing page of one of our reviews and you spend one second, you can glance at the overall percentage score and that will give you a fairly decent amount of information about whether that book is worth reading and whether it’s evidence-based.
Stephan Guyenet:	01:02:30	Then you can take five seconds and you can look at the subscores, the scientific accuracy, and reference accuracy and helpfulness, and that will give you additional information and then you can take one or two minutes and read the summary and that will give you even more information. And so any level you want to engage at is there for you on this review page and of course, we have the full review down below, which is lengthy and explains exactly how each score was determined.
Stephan Guyenet:	01:03:04	And so any level of engagement that you want, you can have on this page. The other cool thing about it is that it allows you to compare between books that you can actually … and this is impossible with normal book reviews, when it’s just a text narrative, you can’t do this. You can’t say, “Hey, this book is more evidence-based than that book because it got a better score on scientific accuracy.” You can’t really do that.
Stephan Guyenet:	01:03:31	So we’re applying a systematic method that, by the way, we don’t claim that this is completely unbiased. There’s no way to be completely unbiased, completely rid ourselves of our personal bias. What we claim is that we have a method that actively reduces bias to the minimum amount that we were able to reduce it to. So it’s not bias free, but when you compare that to a typical book review where there’s no attempt at all through this bias, where the person writing the review is not an expert where they’re just writing about whatever topic suits their fancy, that is a very …
Stephan Guyenet:	01:04:14	I think it’s clear what the advantages are of our method relative to what is typically available. And so we’re really trying to take the next evolutionary step in health and nutrition book reviews to give people better information and to create new incentives in the publishing industry so that publishers and authors are incentivized to write books that are more evidence-based because it’s going to matter to their bottom line.
Stephan Guyenet:	01:04:42	This is really one of the key issues right now with the health and nutrition publishing sphere. I call it an exploding volcano of misinformation because there’s no accountability. You can say whatever you want, there’s no fact checkers. When I wrote my book, there was nobody from the publisher who was checking my facts. They completely relied on me to ensure that my book was factually accurate. I ran it by researchers to make sure that it was accurate because I wanted to do that and not because anyone was looking over my shoulder.
Stephan Guyenet:	01:05:16	And there’s actually an incentive to exaggerate and to make conspiracy stories and to be untruthful to even just make things up. We find a lot of this when we review books, completely unsupported claims. There’s positive incentive to do that because it gets you intention and it gets you more sales. You can come up with some crazy new idea that totally revolutionize the idea of X, Y, Z, even if it’s complete baloney, that is a very effective strategy for selling books.
Stephan Guyenet:	01:05:53	And so we’re trying to reverse that incentive and say, “Hey, you know what? Books that are evidence-based, we’re going to give them a boost. Books that are not evidence-based are going to be demoted and that’s going to affect your sales. It’s going to affect your reputation and we’re creating this incentive structure to make it matter in the publishing industry to improve the information atmosphere that’s around us and hopefully, improve public health as well.”
Dan Pardi:	01:06:22	This is an enormously important endeavor. Information can be very seductive, particularly under the conditions of information asymmetry where you are a non-specialist in the subject. You have a goal to perhaps let’s say lose weight or eat better, and simply good storytelling can lead you in the wrong direction. It can be persuasive and it can put you in a worst place. To have experts review the accuracy of it all, it’s going to help people with limited time that they have to invest in educating themselves towards better options. How long does doing one review take?
Stephan Guyenet:	01:06:58	It’s quite time-consuming because first, you have to read the book and we’re bringing on people who are already reading popular health and nutrition books just because they’re interested in that sphere. However, you have to read the book first and maybe it’s a book you wouldn’t have read otherwise. And then doing the review itself, it’s quite time-consuming. First of all, just the amount of texts is substantial.
Stephan Guyenet:	01:07:24	Second, you’re doing scientific literature searches to test these hypotheses that they’re putting forward and their book or to evaluate the evidence, I should say, underlying them. And then you’re randomly selecting and evaluating 10 references in the book, then you’re evaluating the helpfulness. In terms of hours, I’m not sure exactly how many hours each one of these takes, but if you don’t include the reading of the book, it’s probably at least 10 to 15 hours. Probably more than that.
Dan Pardi:	01:08:03	Probably more than that, then writing it up.
Stephan Guyenet:	01:08:06	So it’s quite time-consuming. This is one of our limiting factors is that it requires a lot of time and energy and so it’s slow to produce these things, but ultimately, I think sometimes if you want to get something right, you just have to take the time.
Dan Pardi:	01:08:20	If somebody in the broader community offers criticism of the review itself, are you guys willing to upgrade it in the face of evidence that you hadn’t perhaps considered?
Stephan Guyenet:	01:08:29	Yeah, absolutely. And this is an important point, we make every effort to do our best to make the information as accurate as possible and so we have affection at the bottom of each of our reviews that says “updates”. And what that is for is correction, noting corrections that we made to the articles since the original version. People can just email us if they find a problem. Authors can also contact us if they believe that something is wrong in our review. They can contact us and if we agree that it’s wrong …
Stephan Guyenet:	01:09:06	The responsibility falls on the primary reviewer, by the way. So this is not going to be me handling all this. The primary reviewer will have the discretion to decide what gets updated. But the other thing is that authors, if they write a response or rebuttal to our review, if that response is respectful and in good faith, we will post a link to it at the bottom so that people can find that at the bottom of our reviews.
Stephan Guyenet:	01:09:39	We don’t want to file in anyone’s voice. At the same time, we decided not to offer the opportunity to actually publish the response on our website because I think that just lends itself too much to abuse, but we will link to people’s response, again, if it is respectful and in good bait, which our reviews are. So we are expecting the same level of acronymity from others that we give to them.
Dan Pardi:	01:10:08	How can people support you and how can people, who are interested in knowing when there’s a new review that comes out, how can we be notified of that?
Stephan Guyenet:	01:10:17	Yeah. Thanks for asking. So, to support, there are a few different ways. One of them is just spread the word. If you think this is a good idea, let everybody know about it on your podcast and on your social media and wherever. Let people know that this resource exists and that’s really going to help us a lot.
Stephan Guyenet:	01:10:35	Second thing you can do is you can donate. So we have donation links on the website, and it’s very important for us to have that influx of money because as I said, it’s very time intensive to write these reviews and so I feel the need to offer a financial incentive to the people who write them. So we need to pay people at least a little bit for their time. These are very busy people who already have full-time jobs. We need to have that financial incentive in place to keep the gears turning. And so the donation would be another to do it.
Stephan Guyenet:	01:11:13	And ideally, if you’re feeling generous, sign up for a monthly contribution because that is really going to be where it’s at for us to have a steady income stream to be able to pay us. And a few people have already done that. Thank you very much for those people who have done that. That is awesome.
Stephan Guyenet:	01:11:32	The third way you can support us is if you want to be a reviewer, you can contact us and I’ll send you an application and we will consider you. So we require that people have a master’s degree or higher or equivalent in a relevant field of science. And so it doesn’t necessarily have to be nutrition. It could be something like meat, setting body fatness or eating behavior, but something that is going to allow you to have a good level of expertise in the types of books that you want to review.
Dan Pardi:	01:12:08	Pen reviewing literature, period.
Stephan Guyenet:	01:12:10	Correct, yeah. And especially we want people who are interested in communicating with the general audience and who have a background in that and are good writers. That’s all important.
Stephan Guyenet:	01:12:23	And then that’s the last thing you asked. How can you stay informed? We just started an email list. Our lead web developer, Dan del Amo, has been doing a great job with the website and he just set up an email list and so on … I think it’s on all the pages, but definitely, on the home page. You just go to the homepage and you scroll down to the very bottom. There’s a window there where you can enter your email address and you will receive updates whenever we write reviews. I will also be announcing reviews on my Twitter account, which is @WHsource.
Dan Pardi:	01:13:00	Perfect. Last thing, how do you recommend people interpret the overall score? Does a score of 90 and above mean it’s high enough quality versus let’s say, something below 50? Because this is relatively new, have you put any thought into a minimum standard across the different buckets for quality? So read if it’s to the right of the score and find a different book if it’s to the left.
Stephan Guyenet:	01:13:27	So we have published four reviews so far and we have one that’s coming up. And so I think we need more time to really feel calibrated on what types of numbers are being generated by this method. But this is definitely an issue that I’m sensitive to and I’m glad you brought it up, and we have taken some steps now to address the issue and what we’ve done is now with the bars, the percentile bars at the top that describe the scientific accuracy and reference accuracy and helpfulness of the book, we have those color-coded based on the percentage that they represented.
Stephan Guyenet:	01:14:05	And so a book that is below 50% the bar is going to be read. 50% to 5% is going to be yellow and above 75% is going to be green, and I think that’s a pretty good guide right there. Based on the books that we’ve done so far, the ones that came out evidence-based, the overall score is in the green, maybe they have one bar on the sub-scores is in the yellow, but generally, they’re green. And the books that we’ve been reviewing that are not evidence-based, they’re usually in the yellow and red.
Stephan Guyenet:	01:14:34	So I think actually even though the kind of cut offs that we have right now are not that well calibrated and pretty simple way of doing it, I think it’s actually working out pretty well so far. And I think we’ll keep it that way until we have a reason to change it.
Dan Pardi:	01:14:53	Great. Is there anything else that you want to cover that you didn’t get a chance to cover yesterday or that you didn’t get to make the points of the degrees that you would have liked to?
Stephan Guyenet:	01:15:02	I think we covered some of the main stuff. I think we really covered some of the main stuff. Just to recap really briefly, I think one thing is that I didn’t really get to fully explained my model. In fact, we didn’t really talk about my model very much at all and that was too bad because that was one of my primary goals, but and I covered some of that stuff. Some of the brain circuit for satiety and for food motivation. That was some of this stuff I wanted to talk about.
Stephan Guyenet:	01:15:31	And then the other thing was this piece of evidence that insulin level is not correlated with weight gain. So people with high and fill in, don’t gain more weight than people with low insulin. That was another piece of key evidence that I wanted to cite, but we covered all that stuff. So I think we’re good.
Dan Pardi:	01:15:50	There’s so much more to be discussed, but I think we covered some of the main areas and I think this is a valuable compendium to the chat yesterday. And hopefully, Joe will have you back on for a conversation with just you and him. So instead of having to debate a counter perspective, you can go more deeply into your perspective on the most important factor in the model. So, hopefully, that will happen.
Stephan Guyenet:	01:16:12	Yeah, I would really like that. I think that would allow me the opportunity to develop my model and also the debate format is challenging because you have this person in your face too, in this case, is quite contemptuous of me and I think I also came across as contemptuous, which wasn’t really my intention, but I think that is how I came across, which is unfortunate and I think that was the learning experience for me. I would love to do that because I think it would come across very differently and I think that it would be very informative in a way that was different than how yesterday was informative.
Dan Pardi:	01:16:52	Well, fingers crossed that that happens and my thinking is that it will. You certainly demonstrated that you know the science very well and could expound on a lot of the different subjects that came up even if you didn’t have the chance to. And also, thank you for putting together that reference list, certainly, a nice service that you provided.
Dan Pardi:	01:17:11	As always, I appreciate the collaboration and your perspective on all this. You’re doing amazing work to affect the perspective of people in the world on how to best take care of their health and regulate their body fat and we appreciate it.
Stephan Guyenet:	01:17:23	Thanks, Dan. I appreciate you too.
Kendall Kendrick:	01:17:27	Thanks for listening and come visit us soon at humanos.me.