"It's Not About The Calories"
Gary Taubes just posted a very informative and interesting blog item about the mistaken notion that calorie consumption and energy expenditure tell us anything meaningful about why we get fat or lose fat:

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.

He talks about a thought experiment with an imaginary set of twins:

Our imaginary twins will be perfectly happy anyway because we say so.) We're going to feed them almost 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.

Taubes is the author of two excellent books I highly recommend -- Good Calories, Bad Calories (for the experience reader of science) and Why We Get Fat (more of a layperson's book).

via @DrEades