13 Weeks: The Hard Boiled Egg Theory


People, including a lot of nutritionists and diet doctors, tend to treat people as if they were more or less homogenous all the way through, like a hard boiled egg: some fat on the outside and a metabolism on the inside. So, when they talk about diets and losing weight, they assume that it’s just all stuff going in versus stuff going out of a sort of blob in the middle. This results in the naive picture of weight regulation where the number of kilocalories you eat (measured by burning the food to ash in a calorimeter) goes in, and it’s either burned up or deposited in the egg white as new fat.

Real organisms aren’t that way, of course. When you eat something, there are long chains of complicated processes going on to transform the chicken meat and carrots and noodles in your chicken soup into amino acids, and fatty acids, and various ions in solutions in the bloodstream; a whole bunch (a whole bunch) of free riders are eating the food too, converting it to other forms that they use to breed their own descendants; some of the result of that turns into nutrients in our blood stream, some of it turns into bacteria, and a whole lot of that eventually turns into something I’m far too delicate to mention.

Once it’s in the bloodstream, there are lots of other complicated processes going on. I talked about them a little bit two weeks ago, but it’s worth remembering that sugars cause the body to release insulin, insulin causes adipocytes (fat cells) to store triglycerides, plump adipocytes release leptin, leptin reduces appetite, which means less food and less sugar, which makes the adipocytes release triglycerides, and so on. There is a complicated feedback going on there, and in a lot of people this feedback results in essentially perfect control of body fat and weight.

We tend to forget this, as talk about the “epidemic of obesity” gets around, but the fact that roughly one-third of adults are obese means that roughly two-thirds of adults are not obese. Most of those not-obese people eat the same general diet, live similar lifestyles, go to the same movies, watch TV and drink sugary sodas, and yet they stay more or less skinny.


The homogenous boiled-egg view of metabolism, though, means people don’t think about the regulatory mechanisms, and the prevalence of the straight thermodynamic, calories in and calories out, just push away from the table you fat slobs model of obesity has kept people from really looking more deeply. In my arrogant opinion.

But as T2DM has become more prevalent, that’s changing. I’m looking at a very recent paper with the unwieldy title “KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation”, by Laura R. Pearce and whole raft of others. KSR2 (Kinase suppressor of Ras 2) is a gene that codes a particular protein that’s involved in a lot of different metabolic pathways in cells.

I’ll save describing the process in detail for a science column sometime, but basically the way genes work is that they’re temporarily unwound, and an organelle called a mitochondrion then uses the sequence of amino acids to construct a protein that the body uses to Do Something. A mutation causes a slightly different protein to be constructed, just as a cookie cutter with a dent might make a misshapen cookie. In this particular case, well, here’s what the abstract says:

We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK- ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Here’s the translation: the researchers identified rare mutations of that gene for KSR2. People who have that gene, which is inheritable, exhibit a cluster of symptoms:

  • hyperphagia, they eat too much;
  • low heart rates;
  • reduced basal metabolism, so they use fewer calories than someone else the same size and activity level; and
  • severe insulin resistance.


As a result, people with this genetic flaw are predisposed to type-2 diabetes, and won’t get the same benefits from low-calorie diets, because they have slow metabolisms. What’s more, once fat is deposited in their cells, they can’t re-process it as efficiently as normal people — they find it harder to lose fat once it has been deposited.

It’s an interesting paper, and shows that contrary to conventional wisdom, there are people who really do have a genetic difference that makes them fatter. It also means, as they suggest in the abstract, that there might be possibilties for new therapies based on looking at how that particuloar metabolic pathway works.

What I think is most important, though, is that it’s another sign the scientific community is started to break free of the boiled-egg model, and see that obesity is a real syndrome that’s a whole lot more complicated than simply being a sign of self-indulgence.