I sat in a booth at Chevys Fresh Mex in Clifton, New Jersey, reviewing the latest research into the neurobiology of hunger and obesity. While I read I ate a shrimp and crab enchilada, consuming two-thirds of it, maybe less. With all this information in front of me, I thought, I had an edge over my brain’s wily efforts to thwart my months-long campaign to get under 190 pounds. But even as I was taking in a study about the powerful lure of guacamole and other salty, fatty foods, I experienced something extraordinary. That bowl of chips and salsa at the edge of the table? It was whispering to me: Just one more. You know you want us. Aren’t we delicious? In 10 minutes, all that was left of the chips, and my willpower, were crumbs.
I am not alone. An overabundance of chips, Baconator Double burgers, and Venti White Chocolate Mochas have aided a widespread epidemic of obesity in this country. Our waists are laying waste to our health and to our health-care costs: According to a study published by the Centers for Disease Control and Prevention in 2010, nine states had an obesity rate of at least 30 percent—compared with zero states some 10 years earlier—and the cost of treatment for obesity-related conditions had reached nearly 10 percent of total U.S. medical expenditure. So-called normal weight is no longer normal, with two-thirds of adults and one third of children and adolescents now classified as overweight or obese. Dubbed the Age of Obesity and Inactivity by the Journal of the American Medical Association, this runaway weight gain threatens to decrease average U.S. life span, reversing gains made over the past century by lowering smoking rates and reducing hypertension and cholesterol. We all know what we should do—eat less, exercise more—but to no avail. An estimated 25 percent of American men and 43 percent of women attempt to lose weight each year; of those who succeed in their diets, between 5 and 20 percent (and it is closer to 5 percent) manage to keep it off for the long haul.
The urgent question is, why do our bodies seem to be fighting against our own good health? According to a growing number of neurobiologists, the fault lies not in our stomachs but in our heads. No matter how resolute our conscious plans, they pale beside the brain’s power to goad us into noshing and hanging on to as much fat as we can. With that in mind, some scientists were hopeful that careful neurobiological studies might uncover an all-powerful hormone that regulates food consumption or a single spot where the cortical equivalent of a neon sign blinks “Eat Heavy,” and learn how to shut it off.
Now the idea of a single, simple on-off switch has been replaced by a much more nuanced view. A multitude of systems in the brain act in concert to encourage eating, the latest research reveals. Targeting a single neuronal system is probably doomed to failure as much as the failed diets themselves. Because the brain has so many backup systems all geared toward the same thing—maximizing the body’s intake of calories—no silver bullet will ever work.
“I call it the ‘hungry brain syndrome,’ ” says Hans-Rudolf Berthoud, an expert in the neurobiology of nutrition at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. The brain’s instructions to eat and defend against the loss of fat are prime directives, installed long ago by evolutionary pressure. “The system has evolved to defend against the slightest threat of weight loss, so you have to attack it from different directions at once.”
The path forward seemed simple back in 1995, when three papers in Science suggested a panacea for the overweight, identifying a hormone that made pudgy animals shed pounds, rapidly losing body fat until they were slim. Based on this research, it seemed that doctors might soon be able to treat obesity the way they treat diabetes, with a simple metabolic drug.
Fat cells release that “diet” hormone—today named leptin, from the Greek leptos, meaning “thin”—which then journeys to the hypothalamus, the pea-size structure above the pituitary gland. The hypothalamus serves as a kind of thermostat, setting not only body temperature but playing a key role in hunger, thirst, fatigue, and sleep cycles. Leptin signals the hypothalamus to reduce the sense of hunger so that we stop eating.
In early lab experiments, obese mice injected with extra leptin seemed sated. They ate less, their body temperature increased, and their weight plummeted. Even normal-weight mice became skinnier when given injections of the hormone.
The pharmaceutical industry created a synthetic version of human leptin and launched clinical trials, hoping that leptin would prove as powerful in people as it had been in overweight rodents. But when injected into hundreds of obese human volunteers, leptin’s effect was clinically insignificant. It soon became clear why. In obese humans, as in mice, fat cells already produced plenty of leptin—more, in fact, than those of their thinner counterparts, since the level of leptin was directly proportional to the amount of fat. The early studies had worked largely because the test mice were, by experimental design, leptin-deficient. Subsequent experiments showed that in normal mice—as in humans—increasing leptin made little difference. The brain perceived low leptin levels as a signal to eat more and essentially disregarded high leptin levels, which had caused mice to eat less. Leptin was a good drug for maintaining weight loss but not a great candidate for getting the pounds off up front.
Despite that disappointment, the discovery of leptin unleashed a scientific gold rush to find other molecules that could convince the brain to turn hunger off. By 1999 researchers from the National Cardiovascular Center Research Institute in Osaka, Japan, announced the discovery of ghrelin, a kind of antileptin that is released primarily by the gut rather than by fat cells. Ghrelin signals hunger rather than satiety. Soon, a team from the University of Washington found that ghrelin levels rise before a meal and fall immediately after. Ghrelin (from the Indo-European root for the word grow) increased hunger while jamming on the metabolic brakes to promote the body’s storage of fat.
This discovery opened another line of attack on obesity, as researchers began exploring ways to turn ghrelin off. Some of them looked at what ghrelin did in animal models, but progress has been slow. One idea would create a ghrelin “vaccine,” but clinical trials are still years away.
Seeking a better understanding of the hormone, University of Washington endocrinologist David Cummings compared ghrelin levels in people who had lost considerable amounts of weight through diet with those who shed pounds by means of gastric bypass surgery—a technique that reduces the capacity of the stomach and seems to damage its ghrelin-producing capacity as well. The results were remarkable. The more weight that dieters lost, the greater the rise in ghrelin, as if the body were telling the brain to get hungry and regain that weight. By contrast, the big losers in the surgical group saw ghrelin levels fall to the floor. Surgical patients never felt increases in appetite and had an easier time maintaining their weight loss as a result. (A newer weight-loss surgery technique removes most of the ghrelin-producing cells outright.)
Based on such findings, a ghrelin-blocking drug called rimonabant was approved and sold in 32 countries, though not in the United States. Unfortunately, it increased the risk of depression and suicidal thinking; it was available as recently as 2008, but has since been withdrawn everywhere. As for pharmaceuticals that target other appetite-related hormones, the verdict is still out. One combination drug contains synthetic versions of leptin and the neurohormone amylin, known to help regulate appetite. In one six-month clinical trial, the combination therapy resulted in an average weight loss of 25 pounds, or 12.7 percent of body weight. But the companies developing it decided not to pursue further clinical trials.
Frustrated with tackling the hypothalamus, many scientists went looking at the other gyres and gears driving obesity in the brain, especially in regions associated with sleep. One big leap forward came in 2005, with a landmark paper describing mice with a mutated version of the Clock gene, which plays a key role in the regulation of the body’s circadian rhythms. The mutant mice not only failed to follow the strict nocturnal eat-by-night, sleep-by-day schedule of normal rodents, but also became overweight and developed diabetes. “There was a difference in weight gain based on when the food was eaten, whether during day or night,” says the study’s senior author, endocrinologist Joe Bass of Northwestern University. “That means the metabolic rate must differ under those two conditions.”
Could my late-night hours be to blame for the failure of my weight-loss plans? Four days after my humiliating defeat by a bowl of tortilla chips, I met with Alex Keene, a researcher with a Matisse nude tattooed on his right forearm and a penchant for studying flies. Then at New York University, he was exploring whether a starved fly would take normal naps or sacrifice sleep to keep searching for food. He found that like humans (and most other creatures), flies have a neurological toggle between two fundamental, incompatible drives: to eat or to sleep. “Flies only live a day or two when they’re starved,” Keene told me as we walked past graduate students peering at flies under microscopes. “If they decide to sleep through the night when they’re starved, it’s a bad decision on their part. So their brains are finely tuned to suppress their sleep when they don’t have food and to sleep well after a meal.”
Keene bred flies with mutations of the Clock gene and also of Cycle, another gene involved in circadian rhythms, that caused these genes to produce dysfunctional proteins. He found that the genes together regulate the interaction between the two mutually exclusive behaviors, sleep and feeding, kicking in to suppress sleep when a fly is hungry.
Even when fed, flies without working versions of the Clock and Cycle genes tended to sleep poorly—about 30 percent as much as normal flies. “It was as if they were starving right away,” Keene explains. He also found where the Clock gene acts to regulate the sleep versus feed conflict, a region of just four to eight cells at the top of the fly brain.
“My father is an anthropologist,” Keene told me as we stood in the fly room, its air pungent with the corn meal and molasses the flies feed on. “It’s ironic, right? He looks at how culture determines behavior, while I look at how genes determine behavior. I used to get him so mad he’d storm out of the house.”
Or perhaps it takes an anthropologist’s son to see that the constant availability of cheap, high-calorie chow does not fully explain the magnitude and persistence of the fat problem in our culture. The disavowal of our inborn circadian rhythms, brought on by a 24-hour lifestyle lit by neon and fueled by caffeine, also bears part of the blame. The powerful effect of disordered sleep on metabolism affects humans, too. A 2009 study by Harvard University researchers showed that in just 10 days, three of eight healthy volunteers developed prediabetic blood-sugar patterns when their sleep-wake schedule was gradually shifted out of alignment.
“It’s clear that the way we’re keeping the lights on until late at night, the way in which society demands that we stay active for so much longer, could well be contributing to aspects of the metabolic disease we’re seeing now,” says Steve Kay, a molecular geneticist now at the University of Southern California.
These insights have fostered new forms of collaboration. “Physicians who specialized in obesity and diabetes for years are now discovering the importance of circadian effects,” Kay says. At the same time, “basic research scientists like me, who have been studying the circadian system for so many years, are now looking at its metabolic effects. When so many people’s research from so many areas starts to converge, you know we’re in the midst of a paradigm shift. This is the slow rumbling before the volcano blows.”
It’s now obvious that metabolic pathways regulating fats and carbohydrates are influenced by the circadian clock, says biochemist Corinne Silva, a program director at the National Institute of Diabetes and Digestive and Kidney Diseases. Her goal is to find drugs that treat diabetes and obesity by targeting these time-sensitive pathways.
This past spring, researchers at the Salk Institute and the University of California, San Diego, reported that timing has a notable effect on mice. In the experiment, one group of mice on a high-fat diet could eat at any time. The other group ate the same food, but could feed only at night—a mouse’s normal waking hours. The time-restricted group were leaner. “We are not only what we eat; we are when we eat,” Kay says.
In Keene’s view, the link between sleep and obesity could be put to use right now. “People who are susceptible to diabetes or have weight issues might just get more sleep,” Keene says.
It convinced me. After I visited his lab, I had a new resolution: Rather than focus on how much food I put in my mouth, I would focus on when I ate. I decided I would no longer eat after 10 p.m.
Timing is not everything; the brain has no shortage of techniques to goad us into eating. Another line of evidence suggests that overweight people are wired to feel more pleasure in response to food. They just enjoy eating more. To study such differences, clinical psychologist Eric Stice of the Oregon Research Institute mastered the delicate task of conducting fmri brain scans while people were eating. The food he gave the volunteers inside the tunnel-like scanners was a milk shake. And let the record show, it was a chocolate milk shake.
Obese adolescent girls, Stice found, showed greater activation than their lean peers in regions of the brain that encode the sensory experience of eating food—the so-called gustatory cortex and the somatosensory regions. At the same time, the obese girls sipping milk shakes showed decreased activation in the striatum, a region near the center of the brain that is studded with dopamine receptors and known to respond to stimuli associated with rewards. Stice wondered whether such a pattern might predict an increased risk of overeating and weight gain.
To test his hypothesis, he followed a group of subjects over time, finding that those with reduced activation in the dorsal (rear) region of the striatum while sipping a milk shake were ultimately more likely to gain weight than those with normal activation. The most vulnerable of these girls were also more likely to have a dna polymorphism—not a mutation, per se, but a rather routine genetic variation—in a dopamine receptor gene, causing reduced dopamine signaling in the striatum and placing them at higher risk.
It suggested that people who overeat may be trying to compensate for this anemic dopamine response. Stice was initially surprised by the results. “It’s totally weird,” he admits. “Those who experienced less pleasure were at increased risk for weight gain.” But his more recent studies convinced him that the reduced pleasure is a result of years of overeating among the obese girls—the same phenomenon seen in drug addicts who require ever-greater amounts of their drug to feel the same reward. “Imagine a classroom of third graders, and everyone is skinny,” he says. “The people who initially find that milk shake most orgasmic will want more of it, but in so doing they cause neuroplastic changes that downregulate the reward circuitry, driving them to eat more and more to regain that same feeling they crave.”
Even among people of normal weight, individual differences in brain functioning can directly affect eating behaviors, according to a 2009 study by Michael Lowe, a research psychologist at Drexel University. He took fmri brain scans of 19 people, all of them of normal weight. Nine of the volunteers reported following strict diets; the other 10 typically ate whenever and whatever they wanted. Lowe had all of them sip a milk shake immediately before getting scanned. The brains of the nondieters, he found, lit up just as one would expect, showing activations in areas associated with satiation and memory, as if saying, “Mmmm, that was good.” The chronic dieters’ brains, by contrast, activated regions associated with desire and expectation of reward. If anything, the milk shake made them hungrier.
Desire and cravings are only one part of the weighting game; reining in those impulses also has something to do with it. Eating behaviors are also linked to areas of the brain associated with self-control (such as the left superior frontal region) and visual attention (such as the right middle temporal region). A recent fmri study led by Jeanne McCaffery, a psychologist at Alpert Medical School of Brown University, showed that successful weight losers had greater activation in those regions, compared with normal-weight people and obese people, when viewing images of food.
Stress also affects eating behaviors, according to University of Pennsylvania neurobiologist Tracy Bale. Neural pathways associated with stress link directly to areas of the brain associated with seeking rewards, she found. “Few things are more rewarding evolutionarily than calorie-dense food,” Bale told me a few days after presenting a seminar on the subject at a Society for Neuroscience meeting in San Diego. “Under stress people don’t crave a salad; they crave something high-calorie.” Stress pathways in emotional regions of the brain feed into reward centers, which stimulate the search for a reward. This could be an important insight for drug companies interested in developing new ways to control eating, she says: “We’re not necessarily fat because we’re hungry but because we’re looking for something to deal with stress.”
Aha! Perhaps it was stress that was messing with my new clock-based diet. Back in March 2010, a tree fell on my family’s home during a major storm, crushing the roof, destroying half the house, and forcing us to flee to a nearby apartment. By November, as I researched this story, we had finally moved back into our rebuilt house. With nerves fully frayed, I found myself drawn as never before to the Tick Tock Diner, where the motto literally is “Eat Heavy,” and where the french fries never tasted better. Instead of losing a few pounds to get under 190, by Thanksgiving I had hit 196.
Neuroscience has yet to deliver a weight-loss elixir for paunchy 53-year-old journalists like me, much less for those suffering from serious obesity. But that day will come, Steve Kay asserts, once researchers identify a combination of drugs that work simultaneously on multiple triggers of eating and metabolism, just as hypertension is now routinely treated with two- or three-drug combinations.
Others think a more radical approach will be needed. Since the triggers of obesity lie in the brain, neurosurgeons at West Penn Allegheny Health System in Pittsburgh are attempting to interfere with those triggers directly using deep brain stimulation (dbs). Since 2009 they have performed surgery on three obese patients to implant electrodes that emit rhythmic electric shocks into the hypothalamus. Having failed other medical therapies for obesity, the three agreed to volunteer for dbs, a treatment already approved for treating the tremors and dystonia of Parkinson’s disease. “These patients weren’t eating all that much; it was mainly a problem of having very slow metabolisms,” says Donald M. Whiting, one of the neurosurgeons leading the study. “Our goal was to speed it up.” On the basis of successful animal studies, he adds, “we thought we’d switch on the energy and collect our Nobel Prize.”
All three patients experienced significantly less hunger when the electrodes were switched on, and all regained normal appetite when the electrodes were switched off. Two patients lost more than 10 percent of their body weight over the several months, but Whiting says it’s too early to tell if they’ll keep it off. There are many ways to adjust dbs, he points out. Each electrode has four contact points, and each is adjustable for voltage, frequency, and pulse width. The research team is tinkering with the settings that most effectively rev up metabolism.
“The brain is really pretty smart,” Whiting says. “It tends to want to reboot to factory settings whenever it can. We find that we can reset things for a week or two, but then the brain gets back to where it wants.” Despite the challenges, Whiting remains convinced that finding a safe and effective medical treatment for weight control will be essential to turn the obesity epidemic around—and that no amount of preaching from Oprah, no behavior program from Weight Watchers nor food from Jenny Craig, will ever suffice.
“This mystification that obesity is caused by a lack of willpower or just eating the wrong foods is simply a misconception,” Joe Bass of Northwestern told me. “There is so much social stigma attached to weight that we make a lot of value judgments. The effort in science is to peel back those layers of belief and try to understand things in an experimental, rational mode. Just as we have made progress against heart disease with statins and blood pressure drugs, we will find medications that can safely and substantially lower weight.”
Months after my investigation of the brain-gut connection began, I faced the acid test. In early March I stepped back onto my bathroom scale for a final weigh-in. Rather than slip below 190, for the first time in my life I had tipped, by a single pound, over 200. You might blame it on insufficient exercise or on the cheese and crackers I failed to remove from my late-night work ritual. I’m blaming it on my brain.
