The “Thrifty Gene” Theory

So, we understand a bit of why the U.S. Pimas have so much more obesity (and diabetes) than their Sierra Madre cousins- it’s large differences in activity levels, and perhaps, something to do with diet composition. That explanation still does not really explain why the U.S. Pimas are so overweight; shouldn’t the Pima brain appetite center make adjustments in appetite to compensate for the low activity level? The answer to the question is that maybe the appetite center should compensate, but it doesn’t. Many scientists who study obesity believe that over thousands of years, human genes have been selected that allow “overeating” when food is plentiful. This genetic trait would have important survival value in times of famine- all the lean and mean people would starve to death while those with excellent fat stores would be more likely to survive. This is the so-called “thrifty gene” theory. Whether this is true or not, it seems to make sense. It is also a very scary thought, since it may well be that in the twenty-first century (2001 and beyond), most people around the world do carry these thrifty genes and we don’t know how to make them go away. Maybe the Pimas’ dilemma is that they just have too much of what used to be a good thing?

Implications of the thrifty gene theory

If this thrifty gene business is true, we will need to either wait thousands of years until something happens to decrease fertility in people who carry these genes, or find other ways to deal with our misguided appetite centers (behavior modification, drugs, surgery, etc.) Maybe we should move to the Sierra Madre?

Environmental (non-genetic) causes of obesity: overview

We have spent quite a bit of time discussing genetic factors, theoretical and proven, that might contribute to the high prevalence of obesity in the U.S. In summary, it is very clear that genetic factors are very important but they cannot fully explain why we have so much obesity, and particularly why we have so much more of it recently; I don’t think we can postulate a large upsurge in obesity genes over the past 20-30 years. So, what are the non-genetic factors that might explain our rising BMIs?

Remember the Pimas?

We briefly discussed the Pimas in an earlier posting. They are an indian tribe that started out in the Sierra Madre of Southern Mexico. Over many years, many of the Pimas migrated northward to what is now the southwestern U.S. Many of them live on the Gila River Indian Reservation, just outside of Phoenix, AZ. The Pimas have the highest known prevalence of diabetes (type 2) of any genetic group- about 50%. The Pimas also have a very high prevalence of obesity, including people many people with BMIs over 40. What is particularly interesting about the Pimas is that those who are still living in the Sierra Madre show virtually no obesity and very little diabetes. Yet, the Sierra Madre Pimas consume more calories, on average, than the New Mexico Pimas. What gives? The answer is activity; the Sierra Madre Pimas have to work hard to survive and their levels of physical activity are far higher than in their U.S. cousins.

Another factor that may be important is the diet composition itself. In the Sierra Madre, the Pimas eat mostly what they grow and raise- lots of corn and occasional chicken. The New Mexico Pimas eat what most other people in the U.S. eat- lots of highly processed foods which are high in fat. I know the U.S. diet is not as healthy as the Sierra Madre diet but I am not certain if diet composition itself contributes to the high prevalence of obesity in the U.S. Pimas and non-Pimas. Certainly it is easier to consume lots of calories when one eats lots of calorie dense foods, but that is a different issue.

Up to this point we have been discussing theoretical and known genetic mechanisms that might explain why there is so much obesity around. There is also strong epidemiological evidence. For example, the more overweight the parents, the more likely the child wil be overweight and that the overweight will persist into adulthood. If only one parent is overweight, the risk for the child is increased 6.8-fold; if both parents are overweight, the risk is 8.4-fold. One might argue that such data do not prove genetic causes, since environmental factors could also be to blame. I agree. But, if we look at data from twin studies, rates for overweight in identical twins, even raised apart show nearly 100% concordance- if one twin is overweight, the other is almost certain to be overweight also. The opposite is also true- if one of an identical twin pair is slender, the other twin is almost certain to be slender as well. These relationships do not hold for fraternal (nonidentical) twins. Clearly, genetic factors contribute to obesity and are powerful forces with which to contend. Next entry we will begin a discussion of non-genetic causes, those we are most able to modify.

In this entry, we will continue our discussion of the “why” of obesity. I must confess that I have been a bit “taken” with my human body/automobile analogy and have neglected to even mention calories. A calorie is a unit of measurement for energy and is defined as the the amount of energy needed to increase the temperature of 1 gram (30 grams = 1 ounce) of water by 1 degree Celsius, or centigrade, which is about 2 degrees Fahrenheit. The scientific term generally used for energy units these days, the joule, is not often used in describing food energy. Also, by convention, the term calorie is used to substitute for what is really a kilocalorie, 1000 calories. In this discussion we will use the term calorie but we really mean kilocalorie- don’t worry about it. If you really want to learn more about this calorie stuff, check here.
Calories

So, as we discussed earlier, all foods consist of carhohydrates (“sugars”), proteins, and fats. Carbohydrates and proteins generate 4 calories for each gram consumed and burned up. Fats generate a whoopping 9 calories for each gram. What this means is that the body has devised a fantastic way to store energy and not add enormously to body weight. Back to the automobile analogy, it’s like the difference between gasoline and ethanol. Each gallon of gasoline generates more energy than does a gallon of ethanol (i.e., more miles per gallon). The down side of the large amount of energy stored per gram of fat is that it’s much easier to take in extra calories eating fats compared to carbohydrates and proteins.

Back to Genetic Causes of Obesity

Sorry for the digression. Let’s consider more possible mechanisms by which genetic factors can contribute to obesity. Theoretically, if there are genetic differences in absorption of foods, that would affect body weight. A number of medical disorders and drugs are well known to inhibit absorption of food, but I do not know if there is much solid scientific evidence that healthy people have widely differing capacities for absorbing foods (it would be like an automobile having a leaky gasoline tank).

What about the other side of the equation, the burn-the-calories side? Obviously, with exercise, one burns “extra” calories, but that’s not strictly-speaking a genetic effect. But, there is evidence that people can be divided into “twitchers” and “non-twitchers.” Twitchers are those people who, when sitting still are in motion- fidgeting, drumming their fingers, etc. Recent studies show that twitchers can burn up to 300 calories more per day than non-twitchers. That is an enormous difference in energy consumption; 100 calories, or the equivalent of about 1 slice of bread, translates into 1 pound of fat, more or less, per month. That’s 12 pounds in a year. So, 300 calories per day- you can figure it out! Certain medical conditions and drugs can affect the “twitch rate.” Examples include excesses of circulating thyroid hormone (caused by disease or medication) and Parkinson’s disease (tremors).

Appetite

What about appetite? In my opinion, this is one of the most important genetic factors related to obesity. Appetite and the sense of satiety (fullness) are complicated biological processes, tightly controlled by the brain and gut hormones. There are well-described differences among people in the amount of food necesary to give a sense of fullness. Remember, even a small difference in caloric intake each day will translate into a large effect on body weight over time; eating 50 “extra” calories per day, everything else being equal, will result in weight gain of 60 pounds after 10 years. Depressing thought. So, some people tend to gain weight because their appetite center told them to do it. One of the best examples of this is the Pima Indians. The Pimas are a tribe, originally from the Sierra Madre region in Southern Mexico. Over many hundreds of years, many Pimas migrated north and settled in what is now the southwestern U.S., just outside Phoenix, AZ. The Pimas have been of great interest to medical scientists because they have the highest known prevalence of type 2 diabetes of any ethnic group in the world, about 50 %. They also have a very high prevalence of obesity. The Pimas have been studied, mostly by scientists from the U.S. National Institutes of Health (N.I.H.) who have had a field office in the Phoenix area for many years. the scientists have carried out a series of fascinating studies that have taught us an enormous amount about obesity and diabetes. One of the lead investigators, , Peter Bennett, had the brilliant idea of visiting the Pimas who were still living in the Sierra Madre, to determine if they had as much diabetes and obesity as the U.S. Pimas (the same genetic make-up in both geographic locations. What Dr. Bennett and his team learned was that the Sierra Madre Pimas had virtually no obesity and very little diabetes. In addition, their studies showed that the Sierra Madre Pimas actually consumed more calories each day than did the U.S. Pimas. The difference was in the amount of activity; the Sierra Madre Pimas had to work hard to survive and had dramatically higher energy expenditure than did their U.S. cousins. So here we likely have two factors at work; first the exercise side of the energy balance equation, which is not genetic, and appetite. Whatever the U.S. Pimas ate, even though it was somewhat less than the Sierra Madre Pimas, it was more than they needed to maintain a normal body weight.

Still More Genetic Influences

Finally, we need to acknowledge that there are factors that we do not understand very well. For example, in the 1970s, a medical scientist, Ethan Sims, from the University of Vermont, carried out a series of very interesting studies on Vermont prison inmates. They were the kind of studies that probably could not be carried out these days, since research ethical guidelines have greatly limited the use of prisoners for research. I do not mean to imply that Dr. Sims’ research studies were dangerous. Anyway, he found that there were innate (I can’t think of a better term at the moment) differences in rates of weight gain among individuals given the same amount of excess calories. He also found that there were large differences in the rates at which individuals lost the weight they had gained when the extra calories were discontinued. So, some people are more likely to gain weight and to have difficulty losing weight independent of the calorie intake. I do not know the specific mechanisms involved but they have to be related to either differences in innate efficiencies in burning calories or, possibly some adaptive changes to changes in caloric intake. So, even without any differences in activity levels or caloric intakes, some people are less likely to gain weight than others and less likely to retain extra weight. Those are the kind of genes most of us want to get!

Now we are ready to get into the “meat” (maybe the “tofu” for vegetarians?) of what causes most obesity and contributes to the development of type 2 diabetes. The big picture is that a combination of genetic and environmental factors are to blame. I use the term “environmental” very broadly to include virtually all non-genetic influences such as psychological, socioeconomic, cultural, etc.

How the Human Body Works: The Automobile Analogy

Just for the sake of our discussion, consider the human body as a fine automobile. This automobile has an engine that powers the vehicle, allowing for motion and other activities such as use of a fancy radio, sunroof, etc. The automobile engine is fueled by gasoline (or other fuels, such as ethanol). In the end, nothing much in the automobile works if the engine doesn’t deliver energy; even the battery which stores energy will give out quickly without a working engine. In the case of the human body, there is also an engine. The engine consists of organs, the heart, liver, the kidneys, etc., and more basic cellular processes which we will call the metabolic machinery. The body engine is fueled by food. Food components, protein, fat, and carbohydrate, are ingested and converted into energy for the engine. That which is not used immediately is stored, mostly in the form of fat. So, think of the body as having a fuel tank full of fat instead of gasoline. The more fat the body stores, the longer the body engine can work; with the automobile, the more gasoline in the tank, the more miles (or kilometers) the vehicle will go and/or the longer the accessories will work. Are you with me so far? It’s not all that bad an analogy. is it?

How Well Does Your Engine Perform?

So, both the human body and the automobile rely on their engines to get the job done. In the case of the automobile, the engine can be turned off and restarted whenever. For the body, the engine must never stop running or death occurs. It’s like an automobile engine that idles but never stops, always using up at least some of the energy stores (in the very short-term, the body can mobilize carbohydrates for energy, but in the long run, it’s the fat that provides the lion’s-share). When the body is on “idle,” we call that the basal state. In that situation, most of the energy stores are used to keep the brain working. Enough energy also needs to be made available to generate enough heat to keep the body warm, the heart beating, etc.

So, already you may have some ideas how genetic factors can cause obesity? For example, automobile engines differ in their performance characteristics. One gallon (about 3.8 liters) of gasoline will get a high-mileage automobile pretty far or allow a long period of idling while an eighteen-wheeler cannot go nearly so far or as long a period of time. It’s the same for the human body. Some people require more stored fuel than others to keep things going. They are the lucky ones- they can eat and eat and not put on weight. Others (like the majority of people in the U.S.) have fabulously efficient engines; they can keep things going in the basal state and with activity using very little stored energy.

The actual mechanisms that determine how well individuals use their stored energy are not well understood but there are definite person-to-person differences. This gets into the metabolic rate, which determines how fast the body engine is running. Some people just “idle” faster, using up those fat stores more quickly. We can affect the metabolic rate with drugs (I didn’t say we should). For example, giving people large doses of thyroid hormone, really revs things up and as you would predict, causes weight loss.

Next entry, I will continue the causation discussion, looking at other ways genetic factors can affect the rate at which the body burns up stored fuel.

So far we have discussed the high prevalences of obesity and diabetes and their adverse health consequences. I did not mention the extraordinary adverse economic consequences for both individuals, their families, and the society at-large. This is an important subject, which I will discuss later. In this entry I will move into the sometimes murky world of causation. Up to this point, my comments are based (mostly) on firm scientific data and are not really controversial. I want to start by focusing on obesity and leaving diabetes until later. For now, it is enough to know that type 2 diabetes only rarely occurs without concomitant obesity, even though diabetes is mostly genetically-based.

Endocrine Disorders and Obesity

It is well known that several endocrine gland disorders are associated with obesity. I chose the term “associated” rather than “cause” since obesity can be prevented no matter what, if the individual’s caloric intake is equal to or less than caloric expenditure. Hypothyroidism “causes” obesity by decreasing the caloric expenditure side of the equation. Cushing disease and syndrome, conditions in which levels of the natural hormone cortisol or a related synthetic hormone are elevated, also cause obesity. The mechanisms include increased appetite and altered fat metabolism with deposition of fat in the neck (the so-called “buffalo hump”) and the abdomen. Hypopituitarism with growth hormone deficiency also causes obesity. Here the mechanisms are not well understood but growth hormone deficiency does alter fat metabolism and is often associated with hypothyroidism.

In growing children it is quite easy to tell if an endocrine condition is responsible for the excessive weight gain; each of the 3 conditions mentioned above are associated with poor growth in height.

Miscellaneous Conditions Associated with Obesity

Many other medical conditions/situations are associated with obesity. In some instances, the mechanism for the obesity is known; in most instances, however, the cause and effect relationship has not been well established. For example a number of syndromes, medical conditions described by either the name of the person who discovered the disorder or a name that conveys the most important features of the disorder, are associated with obesity. Many syndromes are not even specific medical disorders, but rather, patients grouped by having certain signs and/or symptoms in common. Examples include the Turner syndrome and Prader-Willi Syndrome. Both of these disorders are now known to be caused by specific chromosomal abnormalities. The specific reasons for the associated obesity are not well understood. Other disorders frequently associated with obesity include Lawrence-Moon-Biedl syndrome and pseudohypoparathyroidism.

Certain drugs are also associated with obesity. In most instances, the mechanisms are related to increased appetite. Examples include some psycotropic drugs, drugs used to treat allergies, and marijuana.

Finally, obesity is associated with any condition that restricts physical activity.

What Else Causes Obesity?

Unfortunately, the conditions discussed above explain only about 0.1% of all cases of obesity (I just made up that number- I don’t really know with any accuracy what the percentage really is, but it’s very low). What about the other 99.9%? I’ll discuss that in my next entry. I’ll give you a hint- think genetics and environment.

In my last entry, I discussed the high prevalences of obesity and diabetes in the U.S. I did not mention that the problems are now world-wide. This should not come as much of a surprise to anyone. Now, it is one thing to have a “problem” such as an obesity epidemic. It is quite another thing if the problem has serious consequences. I can assure you that both obesity and diabetes are serious matters.

Short-term Consequences

Short-term consequences of obesity include: poor self-esteem and other psychological problems; orthopedic disorders, particularly hip and knee problems; pulmonary and airway problems (more asthma and sleep disorders); abnormal lipids (e.g., high triglycerides and cholesterol); gastrointestinal disorders (e.g., gall stones); skin disorders (e.g., a condition called acanthosis nigricans and yeast infections); and type 2 diabetes.

Long-term Consequences

Long-term consequences include: everything in the short-term category plus increased risks for cardiovascular diseases (heart disease and stroke); hypertension; increased risk for cancer (especially colon, breast, and prostate); and the Metabolic Syndrome, often called the Polycystic Ovary Syndrome in women). I could go on and on but you get the point. The consequences of obesity are big time serious. If you don’t believe me, check out an excellent study on the relationship between weight and the risk of heart failure (Kenchaiah et. al., New England Journal of Medicine 347:305-313, 2002). In some instances, it is not entirely clear wheter it is the obesity itself that causes the complication risks, or some other associated factor. For example, the fact that obesity is associated with hypertension and abnormal lipids, may explain the increased risk for cardiovascular disorders. It has been hard to find a large group of overweight people without hypertension and abnormal lipids to study if those patients have the same risks as normal weight people. This is actually a very important question since we do have effective ways to treat hypertension and lipid abnormalities. Maybe we do not need to work so hard to “fight” the obesity, only the consequences? I’m not really sure that argument makes any sense, but it’s a thought. The reasons for the increased risks of developing of cancer are unknown.

The Consequences of Developing Diabetes

I believe it is appropriate to consider the complications of type 2 diabetes also as consequences of obesity since type 2 diabetes is very uncommon without concomitant obesity. The complications include eye disease, kidney disease, nerve disease (all specific to diabetes), and cardiovascular disease (heart disease, peripheral vascular disease, and stroke).

Over the next few entries I will discuss, in some detail (as promised) what have been widely-described in the lay press as “epidemics” of both childhood obesity and diabetes. I will try to answer 3 basic questions: first, how do we define obesity and diabetes, and are these conditions really epidemic?; second, assuming the answer to the first question is “yes,” why are we having these problems?; and third, what can we do about it?

Definitions

First, obesity as a medical condition, is generally defined based on “body mass index,” or BMI. This is a rough measure of one’s weight relative to height and has been widely used to relate weight to health outcomes. It is far from perfect (for example, muscular teens may have high BMIs but look reasonably lean and mean) but is a simple way to get an idea of one’s health risks related to their weight. In adults, BMI can be calculated by dividing the weight in kilograms (weight in pounds divided by 2.2) by the height in meters squared (height in inches X 0.0254). It’s easy with a calculator, but even easier if you understand the metric system, which is very nice. The height should be without shoes and the weight, with only light clothing. For example, a person who is 5 foot 9 inches tall and weighs 180 pounds has a BMI of about 27. Another person who is 5 foot 5 inches tall and weighs 150 pounds has a BMI of about 25. By definition, a BMI in the range 18.5-24.9 is considered healthy; <18.5 is considered underweight; 25-29.9 is considered overweight; and anything higher is considered obesity (levels 35 and higher have even more scary terms to describe them).

It is important to know that these BMI definitions are not used in children since BMIs change with linear growth and age. Most experts use special charts constructed by the Centers for Disease Control (CDC) and define overweight as BMI greater than the 80 or 85th percentile for age; greater than 95th percentile roughly corresponds to an adult BMI of 30 or greater. Most experts advise against using the term "obesity" when referring to children who are overweight, I guess, to avoid hurting someone's feelings?- go ahead and call the grown-ups obese if you want to.
The Ugly Statistics

Based on BMI data, many many children in the U.Ss and their parents are overweight. Recent data suggest that more than 60% of adults are overweight or obese, and roughly 40% of children are above the 85th percentile and 25% above the 95th percentile (of course, based on statistics, only 5% of children should have BMIs above the 95th percentile). No matter how we look at the data, the majority of adults in the U.S. are overweight, and many children are too. Of course, it can be tricky using normative data to define a disorder, such as overweight or obesity. One could argue that we should define new norms based on current population BMIs. That argument is not a very good one though because the current definitions of overweight and obesity are based (mostly) on health care outcomes. For example, what are the long-term health risks associated with a BMI of 32 vs. 23? Answer: greater.

Trends

Whatever BMI cutoffs one uses, there has been a dramatic increase in overweight/obesity in adults and in children. The increase has been relentless over the past 30 years, but dramatically greater over the past 10-20 years. It is unclear if things have leveled off over the past 2-3 years (The CDC would not like that as it might have a negative impact on their funding to fight obesity-that’s maybe not a very fair comment by me?). As we will discuss later, the consequences of obesity (from now on I’ll use that term as a general one, to include all degrees of overweight, from pleasantly plump to who knows what) are very serious, both to the health of the individual, and the health of our economy.

What Does This Have To Do With Diabetes?

I haven’t really said a word about diabetes yet. Type 2 diabetes is a medical condition characterized by high blood sugar (glucose) levels and risks for serious complications of the eyes, kidneys, nerves, heart, and blood vessels. This condition is typically genetically-based but does not generally occur unless the individual is overweight. So, what would you guess has happened to the prevalence (frequency) of diabetes during our obesity epidemic? You guessed it- more and more diabetes, paralleling the increase in obesity. Recent data suggest the prevalence of diabetes in the U.S is just under 10% with much higher levels in certain ethnic groups (Blacks, Hispanics, Pacific Islanders, Native Americans, etc.). In people over 60, the prevalence is more than 20%. This is all quite extraordinary. We are even seeing quite a bit of type 2 diabetes in children now; this disorder used to be almost exclusively an adult disorder. Now, some pediatric diabetes centers are reporting that 20% or more of their children with newly-diagnosed diabetes have the type 2 variety (they are all quite a bit overweight, as you would expect). I agree that we are seeing more type 2 diabetes in children in association with more overweight, but I believe the condition is being way overdiagnosed- I don’t doubt that it’s diabetes, but in many cases it’s typical type 1 diabetes (what children usually get) and overweight, not type 2 diabetes and overweight. In my experience, cases of type 2 diabetes in childhood rarely occur before the teen years, even in the face of considerable overweight. It happens, but not a often as news report would suggest. We’ll come back to this issue later- it’s not so important for our current discussion.