Diabetes Forecast

How Hormones and the Brain Affect Your Appetite and Weight

Illustration by Haleigh Eason

Hormones are molecules that allow the body to communicate with itself. You may be most familiar with insulin, which signals muscle cells to absorb glucose from the bloodstream. Other hormones control or influence everything from sleep and sex to mood, movement, and growth.

Several hormones, it turns out, also play a big role in hunger and its opposite: satiety, the feeling of fullness. Over the past two decades, researchers have learned a lot about how hunger hormones work, and along the way they’ve discovered that there’s much more we don’t yet understand.

Survival of the Fittest

The urge to eat is motivated by a feeling of hunger, which is influenced by factors such as a food’s savory appeal, the body’s fat stores, and its perceived need for energy. “As you get more energy deprived, you get more hungry,” says Zachary Knight, PhD, a researcher at the University of California–San Francisco School of Medicine. Satiety—the “I’ve eaten enough” feeling—is also the result of hormones signaling to the brain.

All of these impulses have deep evolutionary roots. Just as it’s important for the body and brain to work together to make sure you eat, systems have also evolved to make sure you don’t eat too much. Feeding was just one behavior that kept our distant ancestors alive, similar to hiding from predators, migrating, or mating—fat is important for fertility and surviving famines, after all. But at the same time, someone who spent too much time eating wouldn’t survive. The regulatory system we evolved so long ago still manages our eating impulses today. “The [person] constantly has to be weighing what is most important for survival,” says Knight. “You want the system to be sensitive to your real need so you can evaluate what you need to be doing.”

Hunger Hormones

For decades, scientists have been researching the role of two hormones in regulating hunger, food preferences, and satiety. Called leptin and ghrelin, the two compounds act as signals from the body to the brain and seem to regulate appetite and satiety.

The discovery of leptin’s role in weight gain was based on a simple experiment in mice with a mutation that “knocked out” the gene that tells fat cells to produce leptin, leaving the rodents incapable of making leptin by themselves. When leptin-free mice were injected with the hormone, they kept their weight stable and healthy. But leptin-free mice who weren’t given the hormone ate too much and became obese. The natural conclusion: Leptin was keeping the mice skinny, suppressing or regulating their appetite. High levels of leptin, it was thought, tell the brain “enough,” producing a sated feeling. Low levels, on the other hand, were connected to feelings of hunger.

Think of the hormone as a radio signal that’s emitted by the fat cells and picked up by the brain. The message? You’ve got enough energy stored in the form of fat. Fully loaded fat cells equal a strong leptin signal. When the brain stops receiving the leptin transmissions, it concludes that fat stores are low—and pushes the body to replenish them by making you feel hungry.

Randy Seeley, PhD, is a University of Michigan scientist who’s been studying hormones and obesity for decades. To Seeley, one of the most remarkable things about this elaborate signaling system is how well it works. Like a plane on autopilot, the body takes in different variables, from how much we’re exercising to the calorie content of the food we’re eating. Then, by making us feel more or less hungry, or speeding up or slowing down our metabolism, the hormones interact with the brain to make tiny course corrections to keep us within the right weight range. “It’s a combination of all these signals that allows you to be that accurate,” Seeley says. “It’s amazing that we’re not more obese than we are.”

Consider this: Typical restaurant meals are 200 calories larger than they were two decades ago. Yet the average weight gain among American adults is only a pound each year—the equivalent of 4,000 extra calories. That means that over the course of a year, the average American adult consumes only 11 excess calories a day. In other words, we’re kept almost exactly on target by an extraordinarily complex system of hormones and brain signals.

Seeley says the system of hunger hormones may even be causing us to leave food on our plates as portion sizes grow. Meanwhile, our metabolism compensates and burns more energy. Though Americans are 15 pounds heavier on average than they were 20 years ago, given the increase in portion sizes and time spent sitting down, we could be far heavier, Seeley argues.

Lost in Transmission

Yet even this finely calibrated system is failing to keep up with modern-world challenges, where calories are easy to come by and moving about—thanks to sedentary jobs—is not.

The deeply entrenched leptin response also helps explain why dieting is so hard. When you drop pounds, your body has fewer fat cells, and therefore less leptin. That makes for a weaker “radio signal” to the brain. “If you reduce a 200-pound person to 150 pounds, the [leptin] signal isn’t strong enough for the [brain’s] receiver,” says Columbia University Medical Center geneticist Rudolph Leibel, MD, a pivotal figure in the initial discovery of leptin more than 20 years ago. “What the receiver perceives is that there’s not enough fat in my body to generate a sufficient signal.”

Until weight goes back up to the levels the brain is used to, the lower leptin levels produce a sort of panic in regions of the brain responsible for hunger and satiety. “It’s a very critical system in evolution,” Leibel says, “designed to preserve body fat disturbed when we reduce body weight to treat [type 2] diabetes.” The brain is interested in making sure there’s enough energy on board in the form of stored fat, so people who have lost weight get signals saying they don’t have enough body weight. In effect, the body responds to dieting or weight loss by pressuring the brain to put pounds back on.

Leptin in Action

When it was identified in 1994, researchers thought that leptin would act as a simple switch that would let doctors turn off hunger pangs, solving the problem of obesity—and potentially preventing millions of people from developing type 2 diabetes, or putting it in remission. When the gene responsible for producing leptin was identified, it was hailed as a blockbuster discovery that the prestigious science journal Nature publicized on its cover. Amgen, a California-based pharmaceutical company, bought the patent for $20 million up front and paid tens of millions more as research on the gene and the hormone progressed.

Early work on the hormone was promising. Researchers pointed to an unusual genetic mutation as a sort of extreme example of leptin’s role. People born without the ability to produce leptin (a very rare condition called congenital leptin deficiency that affects a few dozen people in the world) are constantly hungry and quickly become obese, apparently proving the hormone’s effect. When people with the condition were given leptin injections, they lost weight.

Yet when researchers tried giving leptin to ordinary overweight or obese people as a weight-loss treatment, the experiments were a bust. “When this hormone was originally discovered, there were some who thought this would be the answer to human obesity,” Leibel says. “It turned out it didn’t have that effect in obese or nonobese individuals.” That’s a strong clue that leptin is just one piece in a much larger puzzle that includes genetics, environment, and lifestyle.

In the two decades since the discovery, our understanding of leptin’s likely role has changed. Instead of a “hunger hormone” that suppresses appetite, it has a role in defending body weight. “The reason people who lack it gain weight is [that] the brain is lacking the signal that there is enough body fat, so they keep eating,” Leibel says.

In fact, it’s a lot like the hormone insulin: Just as some people are resistant to insulin’s signals, forcing the pancreas to make more and more, some people are resistant to leptin’s signals. Leptin resistance is most severe in people who are obese, making them more likely to feel hungry and less likely to recognize when they’re full. That complicates the use of leptin as an obesity “cure.” Leptin resistance means no matter how much leptin you add to the system, the body still registers levels as “low.” (People lacking leptin receptors in the brain—another rare medical condition—are as obese as people who don’t produce leptin.)

Leptin is secreted by fat cells and goes to work deep inside the brain. Injecting leptin doesn’t really melt off pounds the way insulin injections bring blood glucose under control. “It’s exactly the same problem, but in a different part of the body that’s much harder to study,” says Knight. He says scientists studying hunger hormones are “decades behind researchers studying type 2 diabetes.”

The Role of Ghrelin

Another well-known hunger-regulating hormone is ghrelin, leptin’s presumed counterpart. Researchers used to believe ghrelin increased appetite in the same way that leptin was thought to suppress it. “Results demonstrated on humans that blood levels of ghrelin were peaking before each of three meals,” says Jacques Pantel, PharmD, PhD, medical research endocrinologist at the French Institute of Health. “It seemed to be leptin’s mirror: More ghrelin meant more hunger.” In one recent study of over 300 people, participants with higher ghrelin levels at the beginning of the study reported more food cravings than participants with lower ghrelin levels—and gained more weight after six months.

For years, researchers worked to find a way to block ghrelin, hoping that turning off the hormone’s signals would prevent feelings of hunger. But experiments in rodents were frustratingly inconclusive. When the genes for ghrelin production were removed from the rodents, the lab animals kept eating—which wouldn’t make sense if ghrelin was responsible for hunger.

Recently, Pantel and a team of other scientists suggested that ghrelin might be doing something else altogether. Rather than making you hungry, Pantel says, ghrelin might be telling the body to get ready to store fat. To test their theory, Pantel and his team used rats with a mutation that made them extra sensitive to ghrelin. They put the rats on a diet, restricting the number of calories they got. The rats with a ghrelin hypersensitivity maintained their body weight better, while rats with normal ghrelin sensitivity, which were fed the same restricted-calorie meals, lost more weight.

Then the researchers increased the amount of chow they fed the rats. That’s when things got really interesting: Both the ghrelin-sensitive rats and the normal rats ate the same number of calories, but the ghrelin-sensitive rats gained more weight. What researchers had interpreted as a hunger signal, in other words, might be something else: Ghrelin, Pantel says, could be making the body more efficient at storing fat, flooding the body before meals to prime the body to store calories and lay the groundwork for weight gain.

New Discoveries

Knight is also on the cutting edge of hunger hormone science. His research uses a new technique that can isolate individual types of neurons in the brain to see which ones are activated by different hormones. The technique involves genetic modification and a sensor just slightly wider than a human hair inserted into a region deep inside a live mouse’s brain.

This has allowed Knight, who won a $1.6 million American Diabetes Association Pathway to Stop Diabetes® grant last year, to see what’s going on in a mouse’s brain in real time. A few years ago, he looked specifically at neurons in the brain region that controls appetite. He expected to show that hunger hormones trigger neurons in the brain that make us want to eat. When we’ve eaten enough, our hormone levels shift, setting off another set of neurons that make us feel full and signal us to stop eating—which has been the standard understanding of how hormones affect the hunger circuits in the brain for decades.

Instead, “as soon as the mouse saw food, the hunger neurons shut off—within a second—and satiety neurons turned on,” Knight says. Sometimes the neurons that signal a feeling of satiety began firing even before the mouse took its first bite. Rather than a simple on/off switch, whatever keeps the mouse eating must be more like a chain reaction that’s set off by hunger hormones and continued in other parts of the brain.

That, Knight says, changes researchers’ perspectives on hunger hormones and the brain. Rather than simply measuring and responding to how much fat the body has stored, Knight’s experiment shows that the mice’s brains are taking in information from their environments as well.

Fatty or sugary foods rich in energy actually activated the mouse’s satiety circuits the fastest. The neurons in the brain “seem to take in sensory information about how energy-rich food is and how hungry the mouse is and make a prediction” that it’s time to begin the process of signaling a feeling of fullness, Knight says.

His early evidence suggests that hormones like leptin may cause you to get hungry in the first place, but just seeing the food may turn on satiety neurons in the brain that begin the process of dialing those feelings back. “We thought there was a hunger neuron that would fire and make you eat,” Knight says. “That was obviously too simple.”

What Lies Ahead

Leptin and ghrelin haven’t panned out as quick cures for obesity, and the overly optimistic predictions about leptin and ghrelin in the ’90s have made hunger hormone researchers cautious about overpromising. An obesity “cure,” the University of Michigan’s Seeley says, may still be decades away—if it’s possible to untangle the cascading signals of our hunger hormones at all.

Instead, Seeley thinks research will someday give doctors a range of tools to help people with their weight, the same way there are now medications to treat illnesses such as hypertension and depression, both of which seemed unconquerable at one time. “Think about where we were in terms of treating high blood pressure 30 years ago. About all you could do was relax and eat a low-salt diet,” he says. “Now we have really effective medications. We’re trying to give physicians more tools in the toolbox to fight obesity.”



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