When a Rat Is Full
If the LH is the hunger center, then the ventromedial hypothalamus (VMH) is the “fullness” center.
Again using rats and probes, scientists discovered that damaging or destroying the VMH caused the rats to eat more and gain weight.
Eventually, however, their eating habits and weight stabilized. In other words, they still maintained a setpoint; it had just risen higher. Kind of like what happens when we diet.
Alternatively, when the researchers stimulated the VMH, the rats stopped eating.
A hungry rat in the midst of a meal would drop the food pellet and ignore the food following a brief burst of stimulation. The researchers concluded that when the satiety center is activated, it produces a feeling of fullness, even overfullness. More than an absence of hunger, this stimulation drives the animal to avoid eating any more food, even if it tastes good.
These experiments suggested that while damaging the LH seems to lower the weight setpoint, damaging the VMH seems to “loosen” the setpoint, making it easier to reset.
It turns animals (including humans) into “finicky eaters,” meaning they’re more responsive to certain influences of food.
For example, if a rat with a damaged VMH is given food it likes, it eats more than a normal rat.
Sooner or later, however, it settles at a stable weight, and, as long as its diet doesn’t change, it remains at that weight and responds to the usual tests of setpoint by doing what it can to remain at that level.
Likewise, if the VMH is damaged and the rat is given food it doesn’t like, it loses weight until it stabilizes at the lower weight.
(By the way, normal rats that are force-fed until they become quite fat become just as finicky as those with damaged VMHs, suggesting that finicky eating is not a direct result of VMH lesions, but occurs when one is above his or her setpoint.)
From Rats to Humans
All this information simply underscores what scientists had already suspected: We have a setpoint and our setpoints can be manipulated.
Even as desperate as many people are to lose weight, sticking an electric probe in your brain and damaging parts of it is going a little too far. That’s why scientists are now hard at work figuring out how to change the signals that go to and from your brain to turn
signals to the LH and turn
the signals to the VMH via drugs or lifestyle changes rather than surgery.
In fact, as you’ll see in chapter 4, there are even specific compounds in foods that can alter these messages, partially accounting for raised or lowered setpoints.
Still skeptical? Well, consider this study in humans.
Researchers pulled together 100 volunteers who had effortlessly maintained a stable weight for six months, an indication they were within their setpoint range.
The volunteers agreed to live in a special hospital ward where their food intake and activity levels were carefully monitored and manipulated.
First they had to gain weight until they weighed 10 percent more than their original weight. Then they had to lose weight until they tipped the scales at 10 percent less than they originally weighed. Whether they started out fat, thin, or somewhere between, the results were consistent: When the volunteers ate so much that they gained an extra 10 percent of their body weight, their metabolism increased by 15 percent. Their bodies were clearly trying to drive their weight back down! And when they ate so little that their weight fell to 10 percent below their starting point, their metabolisms slowed by 15 percent.
Now, how can you possibly doubt the existence of your own setpoint?
Identifying Your Setpoint
Your setpoint is:
• The weight you maintain when you listen and respond to your body’s signals of hunger and fullness.
• The weight you maintain when you don’t fixate on your weight or food habits.
• The weight you keep returning to between diets.
Leptin . . . Your Fat Meter
Now you understand the role the hypothalamus plays in maintaining fat homeostasis, or your own setpoint. But just how does the hypothalamus learn what’s going on in the weight department? After all, it’s not like it forces you to weigh yourself every day.
To answer this question, scientists turned to a strain of mice, called ob/ob mice, with a genetic mutation that kept them fat, eating too much, exercising too little, and burning calories very slowly. If you put them in cages with other mice living under the same environmental conditions (all had the same opportunities for eating and exercise), the ob/ob mice stayed fat while the others stayed slender.
To find out why, a scientist sewed an ob/ob mouse to a “normal” mouse (an experiment called parabiosis), allowing the mice to share the same blood. The result was that the fat mouse returned to average weight, suggesting that something in the blood of the thinner mouse played a role in weight regulation.
Suspecting that few humans would want to be stitched to a thinner human to lose weight, scientists set their sights on isolating the gene that kept the thin mice thin. In 1995, Jeffrey Friedman and colleagues at Rockefeller University in New York located the gene. Turns out this gene was responsible for the production of a hormone called leptin.
Mice that lacked the gene—and didn’t make leptin—were extremely fat.
Friedman hypothesized that the hypothalamus was sensitive to leptin and that when the mouse reached an appropriate weight, leptin traveled to the brain and either turned
the LH or turned
the VMH, causing a release of chemicals that helped maintain the setpoint.
The initial research was exhilarating. When the fat mice were injected with leptin, they lost 30 percent of their body weight in two weeks with no apparent side effects. Their metabolism sped up, they ate less, and they ran around more, suggesting that leptin affected many aspects of the energy balance equation simultaneously. When average-sized mice were given extra leptin, they also lost weight.
Since then, we’ve learned that when fat cells increase in size in a healthy person, they produce more leptin, signaling the hypothalamus to do what it needs to do to slow your eating, increase your activity level and metabolism, and return your fat cells to their previous size.
In other words, leptin acted as the “fat meter” fantasized about in the beginning of this chapter.
As you might imagine, the weight-loss industry went wild over the leptin research, certain that a weight-loss pill was finally within reach. Hello leptin, goodbye dieting.
After all, it made sense: If mice got fat because they didn’t make enough leptin, and mice are genetically similar to humans, then wouldn’t it stand to reason that fat humans also didn’t make enough leptin? Inject them with leptin, the thought went, and the fat would melt away.
The biotech firm Amgen quickly bought the rights to Friedman’s discovery for more than $20 million, with the promise of subsequent payments if leptin proved to be the magic bullet some anticipated. The day after announcing the acquisition, Amgen’s stock sky-rocketed.
Scientists in the know were amazed at this reckless cash outlay as it hadn’t been determined—and didn’t seem likely—that many humans had a gene mutation similar to the ob/ob mice. As any scientist worth her rat pellets can tell you, what’s true in mice isn’t always true in humans.
The clinical trials on leptin were disappointing to say the least. In one, for example, seventy-three fat volunteers injected themselves with leptin or a placebo for twenty-four weeks.
Nearly everyone experienced skin irritation and swelling, and many withdrew from the study because of these problems, leaving just forty-seven to complete the study. Although there was an extreme amount of individual variability, of those who stayed in the study, the eight receiving the highest dose of leptin (which also caused the greatest irritation and swelling) lost an average of 16 pounds (though some individuals actually gained weight), while the twelve taking the placebo lost an average of 3 pounds. Low doses had virtually no effect.
Further studies in both rats and humans showed that weight returned to baseline levels after the leptin injections ended. The euphoria over leptin crashed like a lead balloon.
Yes, leptin is produced in humans, and yes, just as in the mice, leptin travels to the brain where it triggers the release of various chemicals to turn down your appetite, speed up your metabolism, and get you moving more. But, researchers learned, fat people were
producing plenty of leptin, even more than their thinner counterparts. The amazing results seen in the ob/ob mice only worked in the few humans with a similar genetic mutation .
Less than a dozen people have since been discovered to have this mutation.
The difficulty for many humans lies in the decreased sensitivity of the brain to leptin’s effects. In other words, your fat meter is working fine: Your fat cells send leptin to the brain to initiate the steps to turn off your appetite and speed up your energy use, but it’s as if the part of your brain that receives the message is swathed in cotton batting—it can’t “hear” the message very well. Thus, your brain doesn’t do its part by triggering the cascade of effects to reduce appetite, increase physical activity, and supercharge metabolism.
Leptin’s main role appears to be protecting against weight loss in times of scarcity. When your fat stores shrink when you’re dieting, so does leptin production. In response, your appetite increases and your metabolism decreases and you gain the weight back.
The opposite, however, is not as strong. Beyond a certain point, increased weight and the resulting increased leptin production do little to blunt appetite or increase metabolism because you hit a limit in your ability to sense the leptin. In other words, your brain is relatively less concerned with preventing weight gain in times of plenty.
This point is very important to understand, so let me explain it in others terms. Weight gain is relatively easy, but the human body is just not designed to support weight loss. This means that reversing weight gain habits will do a pretty good job of preventing weight gain, though they may not result in weight loss.
Another fact frustrating to many is that people with a history of repeat dieting send out less leptin than they would without that history.
This decrease is one of the mechanisms that explains why many chronic dieters tend to be heavier than those who haven’t attempted weight loss. Your body has reset your setpoint to a higher level. Lucky you—you now have an extra layer of protection so you won’t wither away next time you go on a diet (which the body perceives no differently than a famine). Very effective if you lived in another era, but perhaps not so appreciated amidst today’s plenty.
Though it isn’t the magic weight-loss panacea it was initially envisioned to be, the discovery of leptin was a big advance in understanding weight regulation. We learned that it has an extremely powerful effect on our weight and is the cornerstone of our setpoint mechanism, even if we aren’t sure how to harness this power.
The thousands of studies on leptin also spawned even greater research on the neurocircuitry underlying metabolism and on other hormones and neurotransmitters that support leptin. For example, we discovered that insulin, best known for its role in regulating your blood sugar (more on that in chapter 4), is an important ally, informing your hypothalamus about the amount of energy circulating in your bloodstream from your recent meals. Insulin’s message gets amplified by several other gut hormones and nerves that respond to the volume and type of food you eat and other chemical messengers that are sensitive to sensations such as the stretch of your stomach or the texture or temperature of the food you eat.
In 1999, researchers discovered another particularly powerful hormone, ghrelin, that contributes to strong feelings of hunger. All day, ghrelin concentrations rise and fall in our bodies. Although we’re not aware of these ups and downs, they help drive our behavior on a deeply subconscious level, either moving us toward the table or away from the plate. In recent years, research has also begun pointing to the various diet and lifestyle factors that modify the body’s production of ghrelin and other eating-related signals.