Karl Popper, metabolic advantage and the C57BL/6 mouse
Based on the number of comments I get and the number of questions that come through the email on our website, it seems that there is much confusion about the interplay of calories, the caloric deficit, weight loss, and weight gain. I’ll use this space to expand on my views of these complex and confusing issues.First, let’s look at a concept that will help explain a lot. It’s a concept that Gary Taubes explores in great detail in his book Good Calories, Bad Calories, which, by the way, is available now. (Grab a copy and spend a fascinating couple of days poring over it. The rewards will be immense.) The concept in question is interpretation of the energy balance equation, which looks like this:
ΔWeight = Calories in – Calories out
What this equation basically says is that the change in weight (ΔWeight) equals the number of calories consumed minus the number of calories burned off in the process of daily living.
Most people interpret this equation to mean that it is driven from the right hand side. In other words, if you want to reduce your weight (have the change in weight go in a negative direction) you must either eat fewer calories or exercise more or both. Thus the advice that we have all heard to eat less and exercise more. And, as far as the manipulation of that equation on paper goes, that is a correct way of looking at it. But is that how it works in life?
If we accept as true that this equation is driven from the right side and we couple that acceptance with the certain knowledge that the incidence of obesity is of epidemic proportions, then all we can say is that all these obese people eat too much and don’t exercise enough. In other words, they eat like hogs at the trough and they’re lazy. That is the only conclusion we can draw. And, if that conclusion is true, then the way to treat the obesity epidemic is to make everyone eat less and exercise more.
Problem is, that doesn’t work in the long run. Numerous studies show that people can restrict calories and lose weight…over the short term. They can’t seem to do it over the long haul, however. All the subjects in the Keys study lost a huge amount of weight while on a restricted diet and a lot of exercise, but as soon as the study was over, they gained all their lost weight back plus some, which is what typically happens with overweight people who lose substantial weight dieting. The medical literature is pretty conclusive on the idea that you can’t lose weight by exercise (See Gary Taubes’ article in this week’s New York magazine for a fuller treatment of this subject) because people tend to eat more to compensate for the exercise that they do…and it doesn’t take much overeating to compensate for a fair amount of exercise.
The energy balance equation is much like the Arkansas Razorbacks football team this year: they both look good on paper. But the reality is much different. I don’t know how to explain the Arkansas Razorbacks, but I can make a stab at the seemingly bizarre workings of the energy balance equation.
Instead of looking at the equation as one that can be driven only from the right side, let’s look at it from the position that it may be driven from the left. What if the change in weight drove the amount of calories eaten and the amount of caloric energy dissipated? I can think of one situation where the equation makes perfect sense looked at that way.
Think of teenagers. What do they spend inordinate amounts of time doing? Eating and sleeping, right? Teenagers eat all the time and they’re chronically tired. Given the chance, most of them would sleep until noon or later every day. And just try to get one to help around the house. When you do, what do they say: ‘I’m tired.’ And they are tired. Look at how much they sleep.
If the energy balance equation were driven from the right side, all these teenagers should be fat, fat, fat. And, though childhood and teen obesity is on the rise, most teenagers are still thin and lanky. Why? How can this be with the amount they eat and the amount they lay around the house?
Besides laying around the house, eating everything that’s not nailed down, and being obnoxious, what are teenagers doing? They are growing. The majority of people gain most of their height during their teenage years. To build the bone and muscle required to add several inches of height requires a lot of food. Remember, most of the food we eat goes to maintaining the energy levels we need just to live. We burn up a lot of calories just sitting around staring out the window. Teenagers burn those calories, too, but also have to provide for all the energy needed for growth, and that’s not to mention the raw materials for that growth, which can’t be burned as energy.
In teenagers it’s the change in weight (ΔWeight) on the left side of the equation, i.e., growth, that drives the right side of the equation. They eat more and sleep more because they’re growing. They don’t grow because they eat more and sleep more. Not only do these teenagers grow in height, they grow other ways as well: males have a rapid increase in their muscularity; females put on more fat in all the right places. And it’s not only teenagers. Rats that have been genetically and/or surgically altered gain more weight than those that haven’t. Animals that hibernate increase body fatness around hibernation time even if in captivity and with their food restricted. In none of these situations are the changes driven by the amount eaten.
If the energy balance equation runs that way for teenagers why not for the rest of us as well? What if underlying levels of fatness or genetics or _____ (we’ll fill in the blank later) cause us to eat more and burn less?
If we read interviews with the subjects in the Keys starvation study, we find that although they were worked hard as part of the study protocol, when they didn’t have to work, all they did was lay around and sleep. They were chronically tired. They limited their activity as much as possible to conserve the energy contained in the small amounts they ate. Their tiredness and lassitude was driven by the fact that their Δ Weight had dropped thanks to their semi-starvation diets. Their bodies were trying to compensate for the decreased caloric intake by making them exceptionally tired and decreasing their will to move. They were driving their energy balance equations from the left side.
Almost no evidence exists in the medical literature showing that manipulation of the right side of the energy balance equation does much of anything over the long run. Studies on long-term calorically restricted dieting show that subjects lose weight early on then tend to stop losing weight and then regain what they lost plus some. No evidence exists to show that exercise accomplishes anything in the long run. Sure, there are studies done with subjects in a hospital where they can be watched closely and don’t have to rely on recall to have their diets determined, the so-called metabolic ward studies But these studies are prone to error as well. (We’ll discuss these errors in a later post in more detail) And even if they are error free, they are meaningless as far as free living people are concerned. These same studies were conducted in concentration camps during WWII. Almost all of the prisoners lost large amounts of weight, but, just as with the Keys study, they were chronically hungry, they obsessed on food, they were depressed, they slept at every opportunity and they limited their volitional activity.
So, there you have it. Just go on a concentration camp diet and you’ll lose a lot of weight quickly and easily. The problem is, however, that no one can really go on a concentration camp diet for any length of time unless in a concentration camp. Hunger is too compelling. If you go on a calorically-restricted diet for any length of time (i.e., you’re trying to manipulate the left side of the equation by changing one of the components on the right side) your body kicks in and makes you hungry and sooner or later you’re going to give in. At the same time your body will make you tired, sleepy and lazy, and you will conserve as many calories as possible. Because the right side is driven by the left, you are doomed to failure.
So does this mean that if we’re fat we’re doomed to a lifetime of fatness? Are we captives to the left side of our energy balance equations with no chance for escape?
Let’s take a look at how we can manipulate the left side of the equation to get us where we want to be.
First, let’s look at what’s driving the left side of the equation. What’s making us eat more? What’s making us want to move less? Well, for starters, hunger is making us eat more. That and the ready availability of food. Even if we were a little hungry we probably wouldn’t eat unless the food was at hand. We would have to let our hunger reach a higher level before we would seek out food that cost us a lot of activity to get. If all we have to do is reach into a bag of chips, we can sate our hunger (at least temporarily) pretty easily. If we have to get up and cook something, that’s another story.
Forgetting about the availability of food, let’s focus on hunger. Hunger is nature’s way of telling us that we need to eat. Why would nature tell us we need to eat, though, when we’re carrying 40 pounds of excess fat? A couple of reasons. First, one of the signals that the fat cells are sending telling the brain that they’re full – leptin – is blunted. Another reason is that elevated insulin levels – and virtually everyone with an excess 40 pounds of fat has too much insulin – help drive the hunger response in a number of ways. Too much insulin can drop blood sugar levels, and as we’ve discussed, a falling blood sugar drives the urge to eat. Too much insulin also traps the fat in the fat cells. As MD and I discussed in Protein Power, insulin not only drives fat into the fat cells, it also keeps fat there once it’s in. The cells of the body need constant nourishment, not just that that they receive during the normal three meals per day. The body takes in the excess energy consumed during those meals, converts it to fat and stores it in the fat cells. If all systems are working properly the stored energy is released as needed during the time between meals and distributed to the cells via the blood. If insulin levels remain high, the fat can’t get out of the fat cells. So, the individual cells are starving despite the fact that there is abundant energy locked away in the fat cells.
But what about blood sugar? If the cells can’t get to the fat, can’t they use blood sugar? Sure they can. But where are they going to get it? If they consume what’s in the blood, then that level drops and stimulates appetite. In the presence of elevated insulin levels gluconeogenesis doesn’t operate very well, so it’s tough to make more blood sugar. The body finds itself between a rock and a hard place and puts in an SOS call to the brain.
When the brain gets this message, it cranks up all its hunger machinery and off you go looking for food. You eat some chips or a bowl of ice cream or whatever you can get your hands on. The levels of sugar and fat go up in the blood, the cells are happy for a while, and insulin is busy trying to shove it all away into the fat cells. Soon everything stabilizes back to where it was before you noshed on whatever it was you noshed on. Then the cycle repeats. This disregulated metabolism and hyperinsulinemia is what we fill in the blank above.
Now, let’s look at what happens when you intervene with a low-carb diet. You eat a steak and a few low-carb veggies. Your body gets a big influx of fat and protein and a little bit of carb. None of these foods serves to raise insulin levels a lot, so insulin goes up only a little. But along with the insulin now comes a squirt of glucagon, insulin’s counter regulatory hormone. Glucagon can drive gluconeogenesis to make blood sugar if needed, and glucagon also stimulates the activity of hormone-sensitive lipase, the enzyme that transports fat out of the fat cells (also discussed in Protein Power) .
So now between meals we’re in a situation where the cells can get the nourishment they need, so they don’t send the SOS to the brain, and the brain has no need to tell you to eat. So, for the most part, you’re not hungry. As time goes on and you remain on the low-carb diet, you may actually eat more calories than you need to meet all your cellular requirements. What happens then? The brain can send a message to the body to dissipate more calories. You become more active. Instead of dreading working out, you want to work out. You want to move. Even better, internally, where you can’t even sense it, your mitochondria are allowing protons to drift back across the inner mitochondrial membrane and dissipating excess energy. You activate many futile cycles within the cells that ditch excess energy as heat. In short, you’re eating more calories and losing weight to a greater extent than you were when you were simply trying to restrict calories.
When two groups of subjects both eat the same number of calories (but provided by diets of different macronutrient compositions) and maintain the same activity level, yet one group loses more weight than the other, the group losing the greater weight is said to have a metabolic advantage. Or, more specifically, the diet driving the weight loss is said to provide a metabolic advantage.
Some misguided ‘experts’ have been known to say that there is no such thing as a metabolic advantage, despite it’s having been demonstrated in many studies of free living people. But before we get into why these ‘experts’ are wrong, let’s change gears for just a bit.
Sir Karl Popper was a Viennese philosopher considered by many to be the foremost philosopher of the 20th century. Popper fled the Nazis in the late 193os and went to New Zealand; he then moved to England in 1946, where he became a professor at the London School of Economics. He remained in England until his death in 1994 at the age of 92. During his long career Popper wrote many books and influenced countless scholars. One of his most important achievements was his elucidation of his theory of falsification as laid out in his book The Logic of Scientific Discovery. Many scientists consider Popper’s idea of falsification to be the only major improvement to the scientific method since Francis Bacon came up with the idea.
Although more complex mathematically than it appears on the surface what Popper’s falsification theory does is describes a way in which hypotheses can be stated with accuracy. Remember, an hypothesis is merely a guess or an assertion that requires testing before it can be said to be viable. Hypotheses can be stated in ways that, although they seem reasonable, can never really be tested. Popper wrote that the only way an hypothesis can be considered a valid hypothesis is if it can be falsified.
What does this mean exactly?
Let’s say I come up with the hypothesis that all men must ultimately die. That hypothesis seems reasonable on the surface because no one has lived forever. There is no one living right now that anyone knows of who was born before, say, 1850. So it stands to reason that all men must ultimately die. After all, it jibes with what we’ve observed. But, according to Popper, my hypothesis wouldn’t be very good because it can’t be falsified. All we see when we observe someone die – again, according to Popper – is confirmation of the hypothesis, but never proof. For all we know, there is someone living right now who may never die.
If, however, I change my hypothesis to one that says all men live forever, then I have an hypothesis that can be falsified, so it is a good hypothesis. All it takes is for one man to die, and the hypothesis is disproven. So, since that hypothesis is falsifiable, then it is a valid hypothesis. It’s the same if my hypothesis were that all cats are black. All one would have to do to disprove that hypothesis is to find one white cat.
It seem simplistic but it is important. It has changed the way that scientist state their hypotheses so that they can be falsified. That doesn’t mean that the hypotheses will be falsified, but it’s important to state them so that they can be falsified if such data comes forth.
Now let’s back up to our idea about the metabolic advantage.
Some people claim it exists while others claim that it doesn’t. What’s the truth? We know both groups can’t be correct, so one has to be wrong. The metabolic advantage either exists or it doesn’t. Let’s establish our hypothesis so that it fits with Popper’s concept of falsifiability.
If we hypothesize that there is a metabolic advantage we may have some trouble. Why? Because if we search and search and never find any evidence of a metabolic advantage, all we can say is that we haven’t found it yet. If, on the other hand, we state our hypothesis as follows: There is no metabolic advantage, then all we have to do is find one instance where there is one to disprove that hypothesis. Since that hypothesis can be falsified it is a valid hypothesis. And if we can falsify it, then it’s obverse, i.e., there is a metabolic advantage, is true. Sir Karl would approve.
Now that we have our hypothesis, how do we go about falsifying it? Or at least trying to.
By performing very carefully controlled studies.
We’ll leave the discussion as to why and how for another post, but it should go without saying that metabolic ward studies on humans are fraught with inaccuracies. Why? Because people cheat – even in a hospital. The subjects on Keys starvation experiment were under lock and key and they cheated. Keys dropped some from the study because they cheated. And he threatened others. People on ‘metabolic ward’ are simply inpatients in a hospital. They have visitors. They sneak foods. Subjects participating in free-living studies under report their food consumption; those in metabolic ward studies don’t report. As I say, we’ll go into this in a later post, but just because something is a metabolic ward study doesn’t mean it’s infallible.
What is infallible then? Or at least as infallible as a study on living creatures can be?
Animal studies are pretty much the gold standard for this kind of thing. Lab animals can be kept with whatever amount of food the researchers want to give them. They don’t have visitors, they can’t sneak off to the vending machines and they can’t smuggle in food. Most importantly they are usually all genetically the same and should respond to any intervention in the same way, which can’t be said for human subjects (other than identical twins) in almost any study. Lab animals are excellent study material for evaluation of a hypothesis such as the one we developed.
That’s where the C57BL/6 mouse of the title of this post comes in.
Now I’ve written many, many times over the course of this blog that rats and mice are not just furry little humans. Many experimental results from these animals don’t work the same way with humans, so you’ve got to be careful what you accept as valid as far as humans are concerned. But the laws of thermodynamics DO work the same in all living creatures and in all systems for that matter. So rats or monkeys or mice or armadillos are going to obey the laws of thermodynamics in the same way we humans do. And thermodynamic data we gather from well done animal studies applies to humans just as it does to the animals in question.
A couple of months ago a group from Harvard published a study in the prestigious American Journal of Physiology looking at what happens when diet composition is varied in mice, C57BL/6 mice to be exact.
The researchers divided 32 genetically-identical, 8-week old male mice into 4 groups of 8. Each group was put on a different diet. One group got a high-sucrose, high-fat diet (lucky little buggers since they were all going to die anyway), another got a control diet of regular chow, another got a chow diet that was only 66% of the calories of the control chow diet and the last group got a very-low-carbohydrate ketogenic diet. All the mice got the same number of calories that varied with growth. Here’s how that worked out.
The control mice eating the chow set the caloric consumption for the group. Researchers gave the control mice all the chow they wanted and measured the calories consumed. They then gave that same number of calories to the high-sugar, high-fat group and to the ketogenic diet group. They gave 66% of the control diet calories to the calorically-restricted group. They studied the mice for a little over a month, which is a long time in the life of a mouse.
What were the findings?
The researchers discovered that despite eating the same number of calories as the control mice and the high-sugar, high-fat mice, the mice on the ketogenic diet gained weight at the same rate as those on the calorically-restricted diet. (Remember, mice, unlike humans, continue to grow throughout their short lives, and so will continue to gain weight.) Here is the weight change portrayed graphically.
As you can see from A above, the mice on the ketogenic diet ate the same number of calories as all the other mice did except for the calorically-restricted ones. You can see from B that the mice on the ketogenic diet weighed the same as the calorically-restricted mice despite consuming many more mousy calories. And, finally, you can see from C that the laws of thermodynamics weren’t violated because the mice on the ketogenic diet ran at a hotter temperature than did the other mice.
And I find it curiouser and curiouser that the very diet that provided the metabolic advantage to these mice, the ketogenic diet, is the same diet that has been shown to provide a metabolic advantage to humans.
Intelligent people will look at this tightly-controlled study and say, Hmm, mice that ate a ketogenic diet gained less weight than genetically-identical mice eating the same number of calories but of a different composition. There must be something different about the way a ketogenic diet works because it provides a metabolic advantage, i.e., the animals that followed it gained less than those that didn’t and didn’t do anything volitional to keep from gaining the weight.
At least that’s what the authors of the study said. And one assumes that they are reasonably intelligent. Specifically, they concluded that
feeding of a ketogenic diet with a high content of fat and very low carbohydrate leads to distinct changes in metabolism and gene expression that appear consistent with the increased metabolism and lean phenotype seen. Through a specific dietary manipulation, weight loss can occur secondary to distinct metabolic changes and without caloric restriction. [My italics]
It sounds like a metabolic advantage to me. It sure does. It sure does.
These authors have done other studies with this same strain of mice and found the following:
These data indicate that dietary manipulation is capable of altering energy balance and metabolic state. In these experiments a high-fat, ketogenic diet not only failed to cause obesity but was capable of reversing diet-induced obesity in mice. These data suggest a more complex relationship between fat consumption and obesity than previously thought. Further investigation as to the mechanisms of energy balance in these animals may provide new targets in obesity research.
So, we’ve come full circle. Using the data from these mouse studies we have shown that there indeed is a metabolic advantage in living creatures that doesn’t violate the laws of thermodynamics, and by doing so have falsified the hypothesis (vigorously stated by some) that there is no metabolic advantage. Meaning, of course, that there is indeed a metabolic advantage, which anyone with good sense who has fooled around with low-carb diets realizes.
Karl Popper would be proud of us.