13.5: Obesity

When food is abundant, extra energy is readily stored as body fat. Foods high in fat and sugar (concentrated sources of calories) are especially appealing. In a famine, obese people live the longest. There are genetic tendencies toward obesity, and these are perpetuated in famines because the obese are more likely to survive to have children. The ill effects of obesity usually don’t occur until after the prime childbearing years.

Ironically, our wealth and development provide us with both an abundance of calories and less of a need for them. We are continually encouraged to eat. Food is nearby (refrigerator, vending machines) and appealing (donuts, pizza, cookies, cupcakes).

There are constant reminders (TV commercials, magazine ads, driving by McDonald’s) and “eating occasions” (coffee breaks, birthdays, Thanksgiving, baseball games, movies). Food is easy to prepare (frozen dinners, microwave ovens) and convenient to eat, even while walking (ice cream cones) or driving (dashboard dining).

We’re often hard-pressed to find ways of using the extra calories that we so easily store as fat. We have automatic garage-door openers, electric can openers, power lawnmowers, cars with automatic transmission and power steering, light-touch keyboards, food processors, and remote controls for the TV. With an abundance of food and a dearth of exercise, not only do we grow to our genetic potential in height, but it’s easy to grow to our genetic potential in width as well.

Our situation is really an aberration, relative to low-income countries and human history. Physiologically, we’ve adapted to a scarcity of food, and have an elaborate system to maintain the fat stores that have been essential for human survival.

The size of our fat stores is simply a matter of energy balance. When we use more calories than we take in, we burn body fat to make up the difference—the size of our fat stores goes down. To bring it back up, we eat more or use less. Early man used a lot of calories, and using less wasn’t really an option. Survival depended on searching for food, building shelter, running from predators. What worked was a compelling urge to eat when fat stores fell.

Obesity was rare. There was a lot of exercise and not enough food. Besides, obesity hampered an escape from predators—harder to run fast and harder to hide behind a tree. Our genetic heritage includes only modest physiological controls to limit the amount of fat we store. We weren’t even given an urge to jog around the block when we get too fat.

The Urge to Eat

Hunger is the discomfort we feel when we haven’t had eaten for a while. We feel weak and get hunger pangs (stomach contractions) that become stronger and more frequent and even painful, the longer we go without eating—the body’s message to eat becomes more urgent. “Tightening your belt” (a colloquialism for being more frugal in hard times) temporarily helps relieve hunger pangs, as does drinking cold water or alcohol, smoking, and tasting food without swallowing it.

Appetite is the desire for food, a much more positive sensation than hunger. We don’t have to be hungry to have an appetite (I’m stuffed, but did you say chocolate?). You might say that appetite has more to do with external cues. Overweight people are, in fact, more responsive to external cues—a dish of candy on the table, the clock showing that it’s lunchtime, ads for food and drink, donuts next to the office coffeepot. Studies also show when overweight people have unlimited access to a drab formula- drink as a sole source of calories, they tend to lose weight, whereas those of normal weight tend to maintain their weight.

Satiety is the satisfaction of hunger or appetite. There are feeding, drinking, and satiety centers in the brain. We know this from animal studies in which those areas of the brain are electrically stimulated. So when it’s said, you can lead a horse to water, but you can’t get him to drink, it isn’t quite true. Stimulate the drinking center, and the horse will drink.

Normal stimulation of these control centers is complex. As soon as we start eating, signals are relayed to the brain from various parts of the digestive tract—starting with the tongue—and we stop eating. Well, we’re supposed to, anyway. Unfortunately, not many of us stop eating at two thirds of a Big Mac, even if we’re full. We override internal signals. In fact, the huge increase in the portion size of so many foods is partly to blame for our epidemic of obesity. Instead of “super-sizing,” we need to downsize.

What about long-term controls? Our weight stays remarkably steady over decades, much to the dismay of those who struggle to lose weight only to put it back on again.

In the early 1950s, rat studies suggested that something circulates to the brain to signal how much body fat is stored, and food intake changes accordingly. By destroying the brain’s satiety center, a rat would eat voraciously and become obese. A side section of the rat’s skin was then joined to that of a normal-weight rat, so substances in their tissue fluids could pass between them. The obese rat would keep eating, but the normal rat would stop eating to the point of starvation if it wasn’t separated from its obese partner.

It was hypothesized that the huge fat stores sent out huge amounts of a hormone—an urgent message to stop eating that only rats with an intact satiety center can respond to.

f mice that are obese due to recessive genes* called ob and db. They become obese by overeating, but for different reasons, as shown by connecting them by skin to normal-weight mice. A normal-weight mouse connected to an obese ob/ob mouse ate normally. But the obese mouse ate less and lost weight, indicating that its signal-receiving function was OK—it responded to the normal amount of hormone coming from the normal­-weight mouse. It was concluded that ob/ob mice are unable to make the hormone—they can’t send a “fat storage is full” signal even when they are obese.

In contrast, a normal-weight mouse connected to an obese db/db mouse stopped eating, and the obese mouse kept over-eating, suggesting that the obese mouse made plenty of hormone but couldn’t respond to it. In other words, db/db mice get fat because they can’t respond to the hormone, whereas ob/ob mice get fat because they can’t make the hormone.

The advent of DNA technology resulted in a flurry of more detailed information. In 1994, the gene for this hormone (a protein) was found. The hormone is called leptin and is made in fat cells. In 1995, it was shown that leptin was made in proportion to the amount of body fat, and that administering biotech- made leptin to the ob/ob mouse “cured” the obesity. This caused a tremendous amount of excitement, especially among drug companies who see huge dollar signs next to such drugs.

The db/db mice were found to have a defect in the gene for a membrane protein called leptin receptor. Thousands of obese people have been screened for ob and db mutations. It seems to be rare, and the resulting obesity seems to occur where there’s a lot of intermarriage.** Like the mice, they are of normal weight at birth and become severely obese by overeating.

The few who have such mutations include a pair of obese cousins who have a deletion of a single base (G) in the leptin gene’s base sequence, resulting in little or no leptin production. In 1998, there was a report of 3 severely obese sisters whose defect in the leptin-receptor gene resulted in a shortened amino acid chain that didn’t allow the signaling of the leptin message.

Of course, the hope was that low leptin levels were common, so that obesity might be successfully treated with leptin, just as we treat insulin-deficient diabetes with insulin. It appears that most obese people make plenty of leptin, but have less of a response to it—leptin resistance, perhaps analogous to the insulin resistance of diabetics who are obese and make plenty of insulin. Leptin is now being tested for its effectiveness in treating obesity, to be used much like insulin is used to treat insulin-resistant diabetes—using more insulin to try and break through the resistance.

A wide variety of “anti-obesity” drugs are in the pipeline. A major concern is that such drugs can become so popular that their use spreads beyond those for whom the drugs were intended and tested. Even if serious side effects are rare, they can occur in substantial numbers if there are huge numbers of people taking the drugs. And when people take the drugs to lose weight for cosmetic rather than health reasons, the risk/ benefit ratio goes up. Another concern is that there will be less resolve to eat better and exercise more, both of which are extremely important for health in people, overweight or not.

We aren’t likely to find more “magic pills” like the vitamin C pill that cures scurvy—a safe pill that provides an immediate cure for obesity. Today, our major ailments are much more complex, as are the drugs used to treat them. For all that we know about how the body works, from the kinetics of various enzymes to the single base- changes in our DNA that can cause disease, there’s so much we don’t know. The weight-loss drug dexfenfluramine (Redux) was approved by the FDA in 1996 and was withdrawn in 1997 because, besides raising brain- serotonin levels (Chap. 15) to curb appetite, it unexpectedly caused serious heart valve problems in some people.

One drug being investigated is an “uncoupler” that occurs naturally in brown fat. It disrupts the tight coupling of ATP production to the burning of body fuel (Chap. 9), so that more heat is made instead—a way of getting rid of body fat without having to exercise more or eat less.

Fortunately, drugs are more thoroughly tested today than in the 1930s, when an uncoupler used for weight loss was so effective that the heat produced could exceed the body’s capacity to get rid of it and cause death (oops!). Some uncouplers are found naturally in plants, which raises concern about their possible use as dietary supplements, which, unlike drugs, don’t have to be proven safe or effective before being sold.

We already know that leptin can affect fertility—ob/ob and db/db mice can’t reproduce (their parents carry only one copy of the recessive gene). That a hormone made by fat stores would affect fertility really isn’t surprising. Recall the observation that when body fat gets too low, fertility falls.

Pregnancy and nursing use a lot of calories. Therefore, in a famine, survival of fetuses and infants is especially precarious. The body is sensitive to signals of starvation—from a rise in ketone levels (Chap. 8) to a fall in leptin levels—and reacts to protect itself.

^{*A recessive gene is one that must be inherited from both parents for the trait to appear. Blue eyes, for example, is a recessive trait. The parents could have brown eyes with one gene each for blue and brown eyes.
**When there’s a rare, recessive gene in a family, intermarriage makes it more likely that the offspring will inherit the 2 copies of that gene needed for the trait (in this case, obesity) to occur.}

Genes vs. Environment

For all the discussion about genes, the environment is the main cause of the obesity epidemic in the U.S. The prevalence of obesity has gone from about 15% of our adult population in 1980 to about 42% in 2018—too short a time for genetic changes to be the culprit. The increase in obesity and also the “merely overweight” has occurred across all ethnic, socioeconomic, and age groups.

This isn’t to say that genetics doesn’t play a big part. It does. At the least, we’ve all inherited a compelling urge to eat when hungry. And part of human diversity is the range of genetic influences on disease, e.g., the extra-long lifespan of those with genetically high HDL-levels and the extra-short one of those with the genetically high LDL-levels of familial hypercholesterolemia (Chap. 8). But even at these extremes, environment can hasten or delay disease.

Most of us fall between the extremes. For us, environment (diet, exercise, smoking, drinking, stress, medication, etc.) makes a huge difference. Even normal-weight rats, when given cookies instead of food pellets will overeat. Pets of overweight families tend to be overweight, and we know that isn’t genetic!

The cause of obesity is excess calories—from not burning enough or eating too many. So the remedy is “simply” to get more exercise and eat less. Needless to say, this is very difficult, and much more difficult for some than others.

If you’re inclined to overeat and under-exercise, make it harder to do so. “Store” your chips and candy at the store, so you need to go there to buy it each time you want some. Tell the neighbor kid to come by at 7 PM every evening to go running together. Store your cans of soft drinks in the cupboard, so you either have to drink it warm, or (horrors!) go to all the trouble of getting a glass, filling it with ice, pouring the drink, and returning the glass to the kitchen.

Small changes can add up to help you lose weight, just as they can add up to cause you to gain weight.

Obesity and chronic diseases develop over many years, involve many genetic and environmental factors, and aren’t easy to treat. Even small changes in dietary and living habits can dramatically prevent or delay our most common diseases. Fortunately, there doesn’t have to be a different set of guidelines for each condition, e.g., a good diet and regular exercise lowers the risk of heart disease, cancer, osteoporosis, obesity, and diabetes.