Energy Regulation 1: Do Calories Count? And Who's Counting?

In the last post discussing acylation stimulation protein, I made several references to the various regulatory mechanisms that control energy intake, utilization and storage. My claim is that if all of these are working correctly, the body will more or less maintain itself in a healthy state, as that is presumably the evolutionary point of all this stuff. "Healthy state" includes not becoming obese. My guess is that unless you break one or more of these mechanisms, you would find it very difficult to store much excess body fat, because the body doesn't want that, and tries very hard to avoid it by influencing behavior and metabolism.

As we'll see, there are lots of possible things to break and ways to break them: genetic defects, drugs, disease. But for most of us, the major influence is probably diet, mainly through it's influence on insulin. Insulin is arguably the "master hormone" in charge of energy balance. As we'll see, insulin not only controls of blood sugar, but also acts as a signal to start or stop eating, and signals the amount of stored energy in the form of body fat. Insulin interacts with many other hormonal and nervous system mechanisms, and screwing up insulin balance also potentially fouls up a lot of other things as well; take a look at all of the problems inherent in "metabolic syndrome", and you'll get the picture.

I don't believe obesity is a disease in itself, but rather the symptom of an underlying metabolic problem. To "cure" obesity, you really need to restore the appropriate balance, so that the regulatory systems can operate properly. For instance, some obese people have a genetic defect that causes them to make little or no leptin, a hormone secreted by fat cells which is involved in control of both appetite and fat storage. Once you know somebody has this problem, it can be treated by giving them leptin to make up for their deficit. Type I diabetics (who are not obese) lack insulin, so they are treated with insulin. But Type II diabetics have too much of both leptin or insulin, and reduced response to both. Treating them with either leptin or insulin would not be expected to succeed in restoring their metabolic balance and thus normal bodyweight, an expectation borne out by experience. If you're going to fix a problem, you'd better have some idea of the root cause.

So this is the first in a series of posts to delve into the broad topic of "energy regulation", including feeding behavior, energy utilization, and energy storage. Considerable scientific progress has been made on these topics in recent years, but the understanding is far from complete. I'm going to try and touch on the high points, and hopefully avoid too many technical details (which honestly, I don't completely understand myself). Part 1 will be mostly a setup to the subsequent discussion. At the end of this post, I'll put some links to scientific publications or textbooks used, so you can delve into the details if desired.

There's been a lot of discussion lately about whether or not "calories count" in weight gain or weight loss. Much of the argument surrounding this point seems to be unfortunately misguided, with people taking absolute positions on either side. The reality is more complicated. The short answer to the first question is "Yes, calories do count", but is qualified by the fact that many hormonal and nervous system mechanisms regulate caloric intake, storage, and output. Roughly speaking, these are influenced by caloric content of food, but greater influence is exerted by the composition of those calories. As we go through this series, we'll see several examples where macronutrient composition plays a much larger role in influencing the biological response than does simple calorie content. In short, as far as metabolic regulation is concerned, the oft-repeated phrase "a calorie is a calorie" does not apply.

Thinking about the question "Who's counting calories" starts us down the path of understanding. After all, what organisms in nature consciously count the calories they eat or expend? That's easy: humans, and humans alone. Clearly an animal like a rat isn't keeping a tally like "I ate 5 extra grams of rat chow this morning, did 20 minutes on the exercise wheel to compensate" etc. Somehow, they "just know" how much to eat and be active, and their body adjusts accordingly. It is often stated that humans become obese due to an overabundance of readily available food. But in their natural environment, animals will not become obese regardless of food abundance UNLESS there is some other biological imperative to do so. Foxes don't get fat when there's lots of rabbits around, they make more baby foxes. Storage of excess body fat is again clearly regulated by other mechanisms. Mice, for instance, will lay on bodyfat as winter approaches in anticipation of hibernation. Further, they will store excess fat largely independent of how much or little they are fed. Bears similarly lay down fat stores for winter hibernation. Yet once they pass a certain age, they lose the ability to store enough fat for the winter, regardless of how much food is consumed. So the amount of input calories would not seem to be the major controlling factor in fat storage or loss.

Many recommendations for diet and health are based on a grossly oversimplified view of how food intake is regulated. The fullness of the stomach is widely thought to be the primary regulator. You eat until the stomach is full, food moves into the intestines, where your body sucks up whatever it can at a fixed rate until the stomach is more or less empty. Then you get hungry and eat again. This supposedly happens about once every four hours, leading to the idea of three meals a day during waking hours. This oversimplification spawns silly ideas like drinking lots of water or eating high-fiber foods to make you feel more full on less calories, or even sillier interventions like bariatric surgery. Just a little thought shows these ideas can't be right. If it were, a rat would happily eat wood chips and water until it felt full, and would ultimately starve to death from a lack of energy nutrients. Clearly the rat "knows" the energy content of possible food items, and thus avoids the wood chip diet. And we'll see later that surgery such as gastric bypass does more than simply shrink stomach capacity: it also causes measurable and significant changes in the levels of hormones associated with appetite and energy regulation.

The oversimplified view is part of the web of flawed thinking underlying diet. Obesity is not simply a result of being gluttonous, and weight-loss is not simply a process of curtailing caloric intake. "Willpower" is unlikely to enter in to the equation, unless your plan for avoiding or reducing obesity requires that you fight against millions of years of evolutionary programming, life-preserving impulses, and mechanisms regulating appetite and metabolism. Rats and bunnies and bears don't need willpower if fed their natural diet; but feed them something outside of their evolutionarily defined diet, and their bodies often go haywire, with obesity as one possible outcome. One presumes the same holds for humans. Similarly, I think it's pretty easy to poke holes in the idea that higher brain functions (e.g. "willpower") have the capability to override behavior which is key for survival of the organism. Next time somebody blabbers at you about having "willpower" to lose or keep off excess fat, ask them if they have the willpower to hold their breath until they pass out. Fighting against hunger is, I think, the same thing: you can do it for awhile, but the body isn't going to let itself die, and will sooner or later induce behavior it thinks is necessary for survival. This will hopefully become more clear as we delve into the regulation of diet and metabolism.

Before diving into some of the biochemical details, it might be useful to think of a simple model system which requires similar regulatory capabilities. The hybrid electric vehicle (HEV) seems to be a good one, and has some nice similarities with the body. An HEV takes fuel (usually gasoline or diesel) from an external source, and stores it in the gas tank. It also can store energy in a battery, and when moving also "stores" kinetic energy (the energy of motion). Energy can be used from these various sources as demanded by the usage of the car. When accelerating, gasoline is burned in an internal combustion engine and/or electricity from the battery is used to power an electric engine. Energy can be converted amongst it's different forms. The internal combustion engine can be used to either accelerate the car (increasing kinetic energy) or charge the battery. Kinetic energy can be converted to stored electrical energy through regenerative braking.

All of this requires some regulation, so that you don't store/use too much energy, possibly causing inefficient use or damage. One mechanism is simply mechanical: the gas tank has a maximum capacity. If you try to put in more gas than it can hold, gasoline spills out all over your shoes. The battery has a maximum capacity as well: charge it too much, and it may explode. The car's "brain" (a computer and related electronics) monitors the various systems as well as the energy requirements based on your usage. Thus, if the battery registers as not full, applying the brakes will generate electricity which charges the battery. If the battery is full, then that energy must be "wasted" as heat, because there's no place else to put it. If power requirements exceed that of the electrical motor or if the battery is empty, then the internal combustion engine needs to be turned on.

The human body has many parallels. Fuel is supplied externally, but we can take in multiple types: carbohydrate, fat, protein, and alcohol (though obviously the latter is not recommended). This fuel is stored in the stomach, much like the gas tank. Rather amazingly, unlike an HEV, the body needs only one power plant for all different fuel types: the mitochondria. The body has "batteries" as well. Fat cells can store fat, muscles and the liver store glycogen (the storage form of sugar), and lean tissue throughout the body contains protein, though this is generally used for energy only in emergency situations. Different fuel types can be interconverted: carbohydrates can be changed to fat, protein to glucose, fats to ketones. Excess energy can be wasted as heat. And all of this is monitored and regulated by a combination of the nervous system and glands, to maintain the body in a healthy state over a wide variety of usage conditions, whether sleeping or avoiding becoming a bear's lunch. As humans are omnivores, the system can also deal with a very wide range of different macronutrients from plant and animal sources.

The differences between people and HEV cars are informative as well. An HEV can't go get it's own fuel. Instead, it reports on the fuel status to the driver via the fuel gauge. Humans of course need to obtain their own fuel. The "fuel gauge" is ultimately appetite, which is driven by a complex system of hormones and several parts of the brain. An HEV also uses fuel for only one thing, which is to generate energy. While energy is one main purpose of food intake in humans, humans are also constantly regenerating new tissue and other functional substances like hormones and enzymes. Food provides the raw material for this as well. As we'll see in a bit, these functions, most importantly including growth in children, are also closely tied in to the same systems which regulate food intake and energy metabolism.

The cycle of food intake and energy usage/storage can be broken into several steps. Each of these tends to have several interacting regulatory mechanisms, both hormonal and nervous. The steps are:

• Appetite stimulation, which in turn stimulates food-seeking behavior.
• Initiation of the meal (start putting stuff in your mouth).
• Termination of the meal (stop putting stuff in your mouth).
• Movement of food from the stomach to the small intestine for digestion and absorption.
• Utilization or storage of nutrients.
• When everything eaten is used up, start again.
  

If the regulation of any step is disrupted, we have the possibility of non-optimal health, the most outward symptom of which is obesity. For instance, researchers use several strains of rats and mice which have been genetically modified to be predisposed to obesity. The modified genes affect different regulatory systems, with various different outcomes like overeating, underactivity, increased storage of fat over lean tissue, etc. (the "willpower" gene has yet to be identified.) But the main outcome is the same: obesity. When you break a regulatory mechanism, the animal exhibits some combination of behavioral and/or metabolic changes that cause it to become obese. Conversely, if you repair whatever is broken, or compensate for it's effects, the animals generally lose their obesity and normalize metabolism. Why would it be any different in humans?

Subsequent posts will delve into these regulatory mechanisms more deeply, and explore some possible implications for diet and health. Again, much is unknown in this field, so the best we can do is take what is known and apply rational inference; but I think we'll see that some knowledge of how eating and energy storage are controlled provides a powerful explanatory framework for much of what is observed in terms of obesity, weight-loss, and just general health.

Here are some links to the science papers, if you want to get a head start:

• Reviews on Appetite: a group of 14 papers on the topic
• Neuronal Glucose Sensing: What do we know after 50 years?: A nice (but technical) discussion of how the nervous system can directly detect blood glucose levels, and how this influences other regulatory systems.
• Central Administration of Oleic Acid Inhibits Glucose Production and Food Intake: Similar to the above, but evidence of how the brain detects fatty acids in the blood, and again what effects this has on other aspects of metabolism.
• Attenuation of Insulin-Evoked Responses in Brain Networks Controlling Appetite and Reward in Insulin Resistance: some discussion of how insulin affects reward behavior associated with eating, which in turn informs as to why foods that strongly affect insulin are labeled "comfort foods" and may be addicting.
• Why Zebras Don't Get Ulcers, Third Edition by Robert M. Sapolsky: Good info on endocrine systems, particularly related to stress. Also provides some understanding of how different systems interact and affect each other.
  
• Good Calories, Bad Calories by Gary Taubes
  
• Metabolic Regulation: A Human Perspective by Keith Frayn