This is one of those chatty works that argues what could be said briefly with science, but we are a chatty species. Simply put in Taubes’ Why We Get Fat, and What to do About and in my Why we get fat, I it is a one-two punch, sugar (fructose in particular) and carbs (glucose).  The fructose is slowly stored in the live as fat driven by a high carb diet—the glucose causes insulin to rise.  When the liver becomes fatty, then the regulatory system for insulin mal-functions resulting in the condition insulin resistance, and with excess insulin comes excess hunger and excess fat storage.  With that the body becomes lipophilic.  To rely on population studies without knowing the process behind it entails that there will be contradictory examples. Once the process is understood the pieces fall in place.   Note: ethanol is another path to a fatty liver, especially with a high carb diet.  Being an exercise freak can avoid the fatty liver by driving the fructose to be burnt instead of stored. 

http://garytaubes.com/2012/11/what-would-happen-if-thoughts-and-thought-experiments-on-the-calorie-issue/

Thought experiments are devices of the imagination used to investigate the nature of things…. The primary philosophical challenge of thought experiments is simple: How can we learn about reality (if we can at all), just by thinking? More precisely, are there thought experiments that enable us to acquire new knowledge about the intended realm of investigation without new data?…  [T]hought experiments can disclose nature’s failure to conform to a previously held set of expectations. In addition, they can suggest particular ways in which both expectation and theory must henceforth be revised.

When we announced the creation of the Nutrition Science Initiative (NuSI) in September, I e-mailed information packets and press releases to many of my colleagues in science and health journalism. I included a few who had vehemently and even publicly disagreed with the arguments I’ve made in my books and articles. I was hoping to see them embrace the idea that our conflicting ideas should and could be tested, and any organization that could make this happen would be a good thing and worthy of public support. They all expressed their admiration for the effort in private, although none of them perceived it as worth writing up publicly, at least not until we have experimental results to discuss.

A couple of these journalists took the opportunity to insist that we didn’t really disagree all that much on what we had argued over the years, and they explained why. Here’s how one put it in an e-mail back to me (and I’ve made a few minor changes so that this writer can remain suitably anonymous):

“I think in our hearts we basically agree–I know you believe in calories because you are a scientist. And I know you know that many cultures that consume large amounts of carbohydrate but low fat and relatively low sugar are not fat.  (Japan, for example–and yes, I know they are not all slim, but we both know they have a very low obesity rate.)  Do I think some people get “hooked” on sweets and simple carbs?  Yes, I do.  Do I think that can be a problem for some people, hence steering clear of simple carbs is a good idea for them?  I do, and said so on national radio.  Do I think there is strong evidence that carbs per se (in absence of excess calories) will result in excess weight gain?  No I do not.

As I wrote in […]–sugar ain’t great, nor is excess fat.  Sugar and fat infused foods packaged and “ready to eat” are what has made America obese–sitting around doesn’t help, either.  When you cut out carbs, you cut out most of the fat–yes, you can eat pure whipped cream, but not the cake or ice cream you’d normally put it on–so why bother?  Yes, you can eat fried pork-chops, but not breaded fried pork-chops–or clams or chicken–so that cuts calories a bunch.  You eat a lot less butter when you can’t eat the bread or potato or pasta or cake or pie…etc, etc.  There is only so much “whole chicken and steak” and even full fat yogurt with berries that most of us can stomach. So over time, on average we eat fewer calories when we cut out simple and most complex carbs.”

I thought a lot about this e-mail after I received it, for two reasons. One is the tendency we all have (or at least I have and I do see it in others) to assume that just because we’ve written something, other people have read it or certainly should have read it. If only…

In this case, I addressed the no-bread-no-butter, only-so-much-steak-you-can-eat position at length in Good Calories, Bad Calories (The Diet Delusion, in the UK). I even quoted Jane Brody making this point in the epigraph to Chapter 20 — “Unconventional Diets” — and set it off against a quote from the DuPont physician Alfred Pennington to contrast how the same observation — weight loss and absence of hunger on a diet unrestricted in calories  — could be perceived by one person, Pennington, as a “mighty stimulant to thought on the matter,” and by another, Brody, as a triviality to be dismissed without much conscious thought (as my friend did in the e-mail).

Here’s Pennington in 1954:

Here was a treatment, that, in its encouragement to eat plentifully, to the full satisfaction of the appetite, seemed to oppose not only the prevailing theory of obesity but, in addition, principles basic to the biological sciences and other sciences as well. It produced a sense of puzzlement that was a mighty stimulant to thought on the matter.

And here’s Brody nearly half a century later:

Does it help people lose weight? Of course it does. If you cannot eat bread, bagels, cake, cookies, ice cream, candy, crackers, muffins, sugary soft drinks, pasta, rice, most fruits and many vegetables, you will almost certainly consume fewer calories. Any diet will result in weight loss if it eliminates calories that previously were overconsumed.

So rather than get upset at my journalist friend who either hadn’t bothered to read GC,BC after all these years, or read it and found it thoroughly forgettable, I got to thinking about the other point made in the e-mail: “I know you believe in calories because you are a scientist.”

Ignoring the possible mischaracterization of me as a scientist, this statement is a little ambiguous. I obviously believe in calories as a measure of energy, whatever that means to believe in such a thing. (It’s like believing in miles as a measure of distance.) So that’s probably not what my friend meant. What I don’t believe in is that discussions of caloric consumption and expenditure tell us anything meaningful about why we get fat or why we lose fat, and I believe that the mantra that ‘a calorie is a calorie is a calorie” serves only to direct attention away from the meaningful characteristics of the macronutrients in our diets.

I’ve been arguing that the original sin in obesity research is this belief that our body fat is regulated by the amount of energy we consume and expend. I think this is simply the wrong way to think about obesity and the chronic diseases with which it associates, and it’s because this is the fundamental assumption underlying most obesity research, it’s the reason why we’ve made so little progress. (And to those who think we have made real progress, I suggest they take a look around at the people walking by and reconsider.)

Another way to put this is that I think this energy balance hypothesis of obesity is an incorrect paradigm and it has to be replaced with a correct paradigm before progress will be made. Obviously my friend doesn’t understand this, so it got me thinking about yet other ways to explain it that might get the point across. This led me to a series of thought experiments, or gedankenexperiments as I learned to call them back in the days when I was writing about physics rather than nutrition and health.

The great thing about thought experiments is that they come unfettered by financial, ethical or real world constraints. We can do virtually anything in these experiments and see what we think is likely to happen. And we can do it quickly. So here goes.

Let’s imagine we have a pair of identical twins, unimaginatively named A and B. They’re males, say, and 20-years-old. They’ve stopped growing and both are weight stable when this experiment begins. (Remember we can do anything we like in a thought experiment, so if we say they’re weight stable initially, then they are.) Now we measure their daily energy expenditure. Let’s say they both expend 3000 calories a day. Every day, day in and day out — 3000 calories. Again, this is true of both of them because they’re identical in all respects.

Now the experiment: We’re going to house A and B in our splendidly livable metabolic ward and keep them there for the next 20 years. (Thought experiments also come free of  Institutional Review Boards. We don’t have to worry about whether this is ethical or not. Our imaginary twins will be perfectly happy anyway because we say so.) We’re going to feed themalmost identical diets. Each one is going to get exactly 3000 calories a day so that their intake matches their initial expenditure. If we believe in calories, as my friend might have put it, the fact that we’re matching intake to expenditure and both twins are getting the same intake suggests they will both maintain a stable weight for the duration of the experiment.

But here’s the experimental twist: the diets are not identical, they’re only almost identical. They differ in the macronutrient content of ten percent of the calories. So 2700 calories of the two diets are identical. The other 300 calories of A’s diet will come from sugar — sucrose, to be precise,  molecules of glucose bonded to molecules of fructose. In B’s diet, these 300 calories will come from glucose alone. So A will get 150 calories of fructose that B won’t get, and B will get 150 calories more glucose than A. Other than that the diets are indeed identical with all the macro and micronutrients necessary for the twins to flourish.

Now we run the experiment for 20 years. What happens? Care to guess?  Will A and B still be identical after 20 years of A eating 300 calories of sugar every day that B does not eat?

We know sugar is metabolized differently from the glucose in starch because of the fructose component. Glucose is metabolized by cells throughout the body; fructose is metabolized primarily in the liver. We know the liver will turn some of this fructose into fat and if the fructose is delivered quickly enough (say in liquid form as sugar water), it  likely to cause insulin resistance in the liver, which in turn might cause systemic insulin resistance.  The extra 150 calories of glucose in B’s diet will stimulate more insulin secretion, although for B this will come in the absence of any fructose-induced effects in the liver. One way or the other, A and B will experience different metabolic and hormonal effects, despite eating precisely the same amount of calories in diets that are otherwise 90 percent identical. Their fat cells, for instance, will be on the receiving end of different hormonal and metabolic signals. As Claude Bernard would say, the fat cells would be living in a different  milieu intérieur and this will effect how they change over time.

Another way of asking what happens in this experiment is to ask whether this difference in hormonal and metabolic responses to diets of equal caloric content will have a meaningful effect on, say, fat accumulation and risk factors of chronic disease. Indeed, why would we expect our twins to end up with identical body compositions, weights, and chronic diseases risk factors, when their hormonal and metabolic experiences over those 20 years are indeed different? The question, of course, is are these differences meaningful.

If we’re wedded to the energy balance way of thinking — if we believe in calories, as my friend said — we’re supposed to predict that the twins will end up identical. (That’s certainly what the sugar industry would like us to think. Although the industry might even argue, based on observational studies from the 1980s, that the twin eating sugar will end up leaner and healthier than the twin getting only glucose.)But we’re also likely to maybe hedge a little bit. Okay, maybe the twins will have slightly different body compositions after 20 years. Maybe they’ll even have slightly different chronic disease risks, depending on how this sugar-starch/fructose-glucose trade-off plays out. Surely, though, they’ll weigh the same.  After all, they’re consuming identical calories and these calories are exactly matched to their initial expenditure. So they should end up weighing what they weighed at the get-go and they should both weigh the same. Yes? (And by the way, this thought experiment also negates any effects of food reward or the addictive nature of sugars, because we’re limiting consumption and so even if sugar is addictive and A wants to eat more of it, he’s not getting the opportunity.)

But the fact is even their weight’s can differ, because we’ve only fixed caloric intake. We haven’t fixed their expenditure. Both will get exactly the same number of calories. That’s a condition of the thought experiment. But the different macronutrient composition of A’s diet vs. B’s, can have an effect on fat accumulation and so weight despite caloric consumption being equivalent.

Here’s how: let’s assume two things for the sake of argument. First, the sugar in A’s diet causes A to become insulin resistant. And second, insulin works to put fat in fat tissue. There’s some evidence for our first assumption and the second assumption is in the textbooks; there’s a lot of evidence for that.

Now as A becomes insulin resistant, his pancreas has to secrete more insulin than B’s to handle the equivalent carbohydrate load. So A now might have higher circulating levels of insulin than B. If he does, this means more calories might be fixed in A’s fat tissue than in B’s. Put simply, A might now be getting fatter than B. And as A gets fatter, his body has to compensate for the calories that are being locked away in the fat tissue and for the greater metabolic demands of a heavier body. What does A do?

What A can’t do is eat more, because we’ve fixed his caloric consumption at 3000 calories per day. One option is he could cannibalize his lean mass to feed his growing fat tissue. This can certainly be done without violating any thermodynamic laws. Now A gets fatter while simultaneously losing muscle mass and his weight remains more or less the same. A second option is that A’s body merely expends less energy to make up for the calories being locked away in fat tissue and the greater caloric requirement that comes from being heavier.

Now A gets fatter while his energy expenditure goes down. While B remains in energy balance throughout the experiment — eating 3000 calories a day to match the 3000 calories he expends — A moves into positive energy balance. He’s still consuming 3000 calories every day, but he’s expending less. And the reason he’s in positive energy balance is because he’s amassing fat in his fat tissue and getting heavier. (Although a naive observer, wedded to the energy balance, might decide that A has become a couch potato and that’s why he’s getting fatter. In this case, the direct effect of the sugar is to make A expend less energy and this in turn causes the energy imbalance that makes A fat. The causality is reversed.)

So here’s a possible chain of events in our thought experiment that’s perfectly consistent with the laws of thermodynamics but is inconsistent with the notion that a calorie is a calorie is a calorie: first,  the sugar causes A to be insulin resistant; second, the insulin resistance serves to cause a compensatory elevation of serum insulin levels; third, the elevated insulin causes A to store calories in his fat tissue every day and grow fatter.

If this effect is tiny, say, five calories worth of fat get trapped in A’s fat cells every day, he’ll still put on ten pounds of fat over the 20 years of the experiment and weigh 10 pounds more than his genetically-identical brother eating his almost identical diet. If this fat-trapping amounts to 20 calories a day — still less than one percent of the calories A is consuming — that would amount to forty pounds of excess fat over the course of the experiment. It would still be too subtle of an effect to be observable in the relatively short-term experiments done to date on sucrose consumption.

Now, assuming this did happen, or at least could happen, it would lead us to some other interesting observations as well. For instance, if A puts on this fat above the waist, it will increase his heart disease risk. The more fat he gains, the greater his risk of diabetes. In fact, depending on the size of the effect, he might become diabetic over the course of the study. His brother might not. A’s cancer risk goes up, as well, with his adiposity. So does his risk of getting Alzheimer’s. All without consuming a single calorie more than his twin brother did. In fact, if we run the experiment long enough, the brothers might die of different diseases and one might out live the other by a significant amount.

If you believe this scenario is a possibility, even a likely possibility, as I do, you still believe in the laws of thermodynamics. You’re still thinking like a scientist (as my friend might say). But now, I hope, you can see what I mean by calories being the wrong paradigm. If we believe in calories,as my friend put it, then we believe that the twins end up identical, just as they started, because the quantity of calories consumed in the two diets was identical and it’s quantity that matters, not quality.  What do  you believe?

We’ve started with identical twins, hence the very same genetic make-up. We’ve fed them diets of identical calories. We’ve made a relatively subtle change in macronutrient composition. Do we end up with twins that are still identical; or do we end up with one twin fatter and perhaps sicker than the other? And, keep in mind, as I said, that both twins are limited to 3000 calories a day, and we’re making them eat all 3000, so any addictive effects of the sugar, say, are not relevant. (And if food reward characteristics are meaningful, they have to manifest themselves via the periphery — increasing fat mass, for instance, through central nervous system stimulation of adipocytes — not merely by making us want to eat more. )

Now we can do a host of variations on this experiment. For instance, we can start off with two villages — A and B. Each village has one of each pair of 5000 identical twins. So each sibling pair is identical, but the 5000 sets of twins are as genetically diverse as any 5000 individuals chosen at random. We put  5000 siblings in village A and their 5000 twins  in village B. Now we do the same experiment on this population scale. We measure their energy expenditures. We match intake to expenditure for each pair of twins. Then the twins in village A all get ten percent of their calories as  a sucrose-sweetened beverage. The twins in village B get ten percent of theirs as a beverage with  glucose, not the glucose-fructose mixture that village A is getting.

Now let’s run it out for 20 years. Do villages A and B end up with exactly the same number of obese villagers, exactly the same incidence of diabetes? Heart disease? Cancer? If we run it out for decades, do the two villages have the same mortality rates? The only difference in their diets is the type of carbohydrate that’s sweetening their daily drinks. (And remember, this is a thought experiment: each villager is eating and drinking precisely what we say they’re eating and drinking because they’re under our imaginary control. No propositions need be voted on. We get perfect compliance to our interventions.)

If you believe in the primacy of calories, or you’re a sugar industry spokesperson, then you believe that the two villages start off identical and they end up identical. (Or, for the sugar industry spokespeople, maybe Village A ends up healthier.) If you believe that one village is going to end up fatter and sicker than the other because they’re experiencing different metabolic and hormonal experiences for 20 years, then you’re thinking as I now think and Robert Lustig has argued so publicly. It’s not about the calories; it’s about what those macronutrients do metabolically and hormonally. And who knows what else, maybe the sucrose has an effect on gut biota that the glucose alone does not,or vice versa, and if the two twins develop different bacterial populations in their guts, then this might induce a whole host of other downstream differences that could effect their weight and health.

We can play these thought experiments all day long. That’s the joy of gedankenexperiments. They’re ridiculously inexpensive and we can do them fast. Twenty years in a gedankenexperiment can be instantaneous in reality.

How about this one: instead of feeding twin B (or village B) glucose instead of sucrose, what if he (or it) got dietary fat. So now twin A gets ten percent of his calories as sugar water — pick your poison, so to speak, soda or fruit juice. Now we’re accelerating the delivery method in this thought experiment by making sure these calories are digested quickly. Twin B gets liquid fat, say heavy cream. watered down so that the energy density is effectively identical to the sugar water. So we control for energy density, a factor that the authorities think is key to weight gain. But we dramatically change the macronutrient content of these 300 calories — glucose and fructose calories for A, fat calories for B. Now the hormonal and metabolic responses to these 300 calories are entirely different. Nothing subtle about it. What happens over 20 years? Same body composition, same disease status because the calories are identical? Yes or no?

What if we play more extreme variations with the diets. Rather than play with just ten percent of the calories they consume, let’s play with 50 percent of them.  Twin A (or village A) gets his (or its) calories as a standard American diet, replete with 50 percent carbohydrates, of which, say, a fourth is sugar or high fructose corn syrup as is about the case today in the standard American diet. Twin B (or village B) gets a paleo diet or even a ketogenic diet, same amount of calories, far fewer to almost no carbohydrates, far more fat. What happens? Both twins (or villages) eat precisely the same amount of calories (each or per capita) every day for 20 years. Do they end up identical. Is village A healthier and leaner or village B or neither?

Now let’s change it up entirely, and this will be the last experiment I’ll suggest for the moment. Rather than start with genetically identical twins eating different diets and so generating different hormonal/metabolic responses that way, let’s start with subjects who are not genetically identical, and give them the identical diet. So we can use fraternal twins or siblings, or total strangers as our subjects, but now feed them the exact same diet. We’ll choose our subjects so that they’re the same age, to the  day, the same height and weight and they expend the exact same amount of energy every day (at least when the experiment begins). They’re both equally healthy. And now we feed them the same diet — intake matched perfectly to expenditure — with 10 percent of the calories coming as sucrose. What happens? How do they change over the twenty years of the experiment, given the exact same diet, precisely the same calories, precisely the same physical characteristics, but different genetic make-ups?

The differences in their DNA means they’ll almost assuredly have different hormonal and metabolic responses to the diet. Maybe one does a slightly better job of metabolizing fructose in the liver than the other does. Maybe one secretes a little more insulin in response to the glucose, or is a little more sensitive or resistant to the insulin secreted. Maybe the gut biota in one responds differently. Maybe leptin resistance develops in one but not the other. Anything can happen right, because genes ultimately determine all these responses and their genes are different.

So we’re feeding them exactly the same diet — same quality and quantity — but the hormonal and metabolic responses are going to be different. Their milieu intérieur is going to be different. Maybe a little different as the years go by; maybe a lot. We don’t know.  They may start out relatively identical in relevant physical characteristics, but little by little, they’re going to diverge. Why would we expect them to end up with with the same weight, same fat mass, and even the same chronic disease risk profile?

And if all these things do end up different, would our belief in calories have led us to the same understanding of what happened and why?

If we could do this experiment in real life, it wouldn’t really matter what we believe. Right? We just do the experiment and see how it comes out. (And this is what NuSI hopes to achieve, albeit in far more realistic experiments.) Because we can’t do the experiments, we can do these thought experiments instead and inform our understanding. Time permitting, more will be coming in later posts.

One last note before I conclude here. Let’s go back to our original experiment with twins A and B and their almost identical diets. Imagine, now, as I suggested, that A gets fatter than B and even heavier, because of the effect of the sugar in A’s diet on hepatic metabolism and insulin sensitivity and so serum insulin levels and fat accumulation in fat cells (and maybe all those other factors like gut biota). But A is never able to eat more to compensate for this loss of calories into his fat tissue and his increasing weight, because we don’t let him: we’ve fixed his caloric intake. As a result it’s safe to assume that A would be  hungrier than B is for the entire 20 years. B can eat to satisfy the metabolic requirements of his body; A cannot. How would that manifest itself? Would A at least feel like binging on occasions? Could we create a binge eating disorder that never gets to manifest itself in this particular thought experiment, just by changing the macronutrient composition of the diet?

You can see how thought experiments can lead us to all kinds of conclusions and (at least hypothetical) observations that might not be intuitively obvious otherwise.

I could go on. I’m hoping the point is clear.

Getting back to my friend’s e-mail: Yes, I believe that calories are a useful measure of the energy contained in the foods we consume and a useful measure of the energy our bodies expend. (Just as I believe miles are a useful measure of how far I have to travel to get, say, from Oakland to Los Angeles.) Yes, I believe in the laws of thermodynamics and I believe, as I say in both my books, they always hold true. That’s why we call them laws. But, no, I do not believe that we can learn anything useful about why people get fat or why they get the diseases that associate with getting fat, by focusing on the calories they consume and expend. It’s not about the calories.