A New Suspect in the Obesity Epidemic: Our Brains

The urge to eat too much is wired into our heads, in several complicated and overlapping ways. Tackling obesity may require bypassing the stomach and short-circuiting our brains.

By Dan Hurley|Tuesday, August 23, 2011
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10:19 p.m. on a Monday evening in October, 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 economy: 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 risk factors from smoking, 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 convincing our conscious plans and resolutions, 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 studies of the brain 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,” all the better to shut it off.

After extensive research, the idea of a single, simple cure has been replaced by a much more nuanced view. The latest studies show that a multitude of systems in the brain act in concert to encourage eating. Targeting a single neuronal system is probably doomed to the same ill fate 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 single 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 prime directive to eat and defend against the loss of fat emerged early in evolution, because just about every creature that ever trotted, crawled, swam, or floated was beset by the uncertainty of that next meal. “The system has evolved to defend against the slightest threat of weight loss, so you have to attack it from different directions at once.”

With the obesity epidemic raging, the race for countermeasures has kicked into high gear. Neuroscientists are still seeking hormones that inhibit hunger, but they have other tactics as well. One fruitful new avenue comes from the revelation that hunger, blood sugar, and weight gained per calorie consumed all ratchet up when our sleep is disrupted and our circadian rhythms—the 24-hour cycle responding to light and dark—thrown into disarray. All this is compounded by stress, which decreases metabolism while increasing the yen for high-calorie food. We might feel in sync with our high-tech world, but the obesity epidemic is a somber sign that our biology and lifestyles have diverged.

Seeking Silver Bullets, Shooting Blanks

The path forward seemed so simple back in 1995, when three papers in Science suggested a panacea for the overweight: A hormone that made animals shed pounds, rapidly losing body fat until they were slim. Based on the 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—to begin a journey across the blood-brain barrier 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 given extra leptin by injection 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.

Once the pharmaceutical industry created a synthetic version of human leptin, clinical trials were begun. But when injected into hundreds of obese human volunteers, leptin’s effect was clinically insignificant. It soon became clear why. In humans, as in mice, fat cells of the obese already produced plenty of leptin—more in fact than those of their thin 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—increases in leptin made little difference to the brain, which looked to low leptin levels as a signal to eat more, essentially disregarding the kind of high levels that had caused deficient mice to eat less. This made leptin 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 talk the brain into turning hunger off. By 1999 researchers from Japan’s National Cardiovascular Center Research Institute in Osaka had 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 to the hypothalamus. Then, in 2002, 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.

So began another line of attack on obesity. Rather than turning leptin on, researchers began exploring ways to turn ghrelin off. Some of them began looking at animal models, but progress has been slow; the concept of a ghrelin “vaccine” has been floated, but clinical trials are still years off.

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. For dieters, the more weight 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 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. It remained available as recently as 2008, even though it also increased the risk of depression and suicidal thinking; it has since been withdrawn everywhere. The verdict is still out on a newer generation of combination pharmaceuticals, including one that contains synthetic versions of leptin and the neurohormone amylin, known to help regulate appetite. In a six-month clinical trial, the combination therapy resulted in an average weight loss of 25 pounds, or 12.7 percent of body weight, with greater weight loss when continued for a full 52 weeks; those who stopped taking the drug midway regained most of their weight.

The Circadian Connection

The limited results from tackling the hypothalamus sent many scientists looking at the other gyres and gears driving obesity in the brain, especially in regions associated with sleep. The first big breakthrough came in 2005, when Science published a landmark paper on 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 eat-by-night, sleep-by-day schedule of normally nocturnal mice, they 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 the undoing of my weight-loss plans? Four days after my humiliating defeat by a bowl of tortilla chips, I met with Alex Keene, a postdoctoral researcher at New York University with a Matisse nude tattooed on his right forearm and a penchant for studying flies. His latest study asked 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 yet 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.”

For a major study published last year, Keene bred flies with dysfunctional mutations of the Clock gene and also of Cycle, another gene involved in circadian rhythms. 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. Keene went even further, pinpointing where, amid the 100,000 or so neurons in the fly brain, the Clock gene acts to regulate the sleeping-feeding interaction: 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.”

Perhaps it takes an anthropologist’s son to see that the excess availability of cheap, high-calorie chow cannot fully explain the magnitude and persistence of the problem in our culture. The rebellion against our inborn circadian rhythms wrought 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 has been seen not just in flies but also in humans. A 2009 study by Harvard University researchers showed that in just 10 days, three of eight healthy volunteers developed prediabetic blood-sugar levels when their sleep-wake schedule was gradually shifted out of alignment.

“It’s clear from these types of studies 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 at the University of California, San Diego.

These insights have fostered collaboration between once-diverse groups. “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.”

This past April, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health organized a first-ever national conference focused solely on how circadian rhythms affect metabolism. “What has become obvious over the past few years is that metabolism, all those pathways regulating how fats and carbohydrates are used, is affected by the circadian clock,” says biochemist Corinne Silva, a program director at the NIDDK. Her goal is to find drugs that treat diabetes and obesity by targeting circadian pathways. “The mechanisms by which circadian rhythms are maintained and the cross talk with metabolic signaling are just beginning to be elucidated,” she says, but they should lead to novel therapeutic approaches in the years ahead.

In Keene’s view, the newfound 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. I get only about six hours of sleep myself. I usually run in the middle of the night. I’m not a morning person,” the enviably thin, 29-year-old Keene states.

My visit to his fly room convinced me to try a new angle in my quest to get under 190 pounds: Rather than focus on how much food I put in my mouth, I would focus on when I eat. I decided I would no longer eat after 10 p.m.

The Pleasure Factor

Timing may be everything for some folks, but it wasn’t for me. No wonder: The brain has no shortage of techniques to goad us into eating. Another line of evidence suggests that the brains of overweight people are wired to feel more pleasure in response to food. Sleep deprived or not, they just enjoy eating more. To study such differences, clinical psychologist Eric Stice of the Oregon Research Institute mastered the delicate task of conducting fFMRI brain scans while people were eating. The food he chose to give 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 compared with 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, archipelagoes of neurons that reach across different structures in the brain. 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, even among normal-weight girls, 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. “Individuals may overeat,” Stice and his colleagues concluded, “to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.”

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 have 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 showed activations in areas of the brain associated with desire and expectation of reward, however. If anything, the milk shake had made them hungrier.

“What we have shown is that these chronic dieters may actually have a reason to restrain themselves, because they are more susceptible than average to overeating,” Lowe says.

Yet inborn differences in hunger and desire, too, turn out to be only part of the weighting game. 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 Brown Medical School, showed that successful weight losers had greater activation in those regions, compared with normal-weight people and obese people, when viewing images of food.

The effects of stress on eating behaviors also has a neurobiological basis, according to University of Pennsylvania neurobiologist Tracy Bale. She showed that neural pathways associated with stress link directly to areas of the brain associated with seeking rewards. “Few things are more rewarding evolutionarily than calorie-dense food,” Bale told me a few days after presenting a seminar on the subject at last fall’s Society for Neuroscience meeting in San Diego. “Under stress people don’t crave a salad; they crave something high-calorie. It’s because those stress pathways in the limbic system feed into the reward centers, and they drive reward-seeking behaviors. What that tells us is that in addition to drug companies’ trying to target appetite, they need to look at the reward centers. 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 latest, clock-based diet. Back in March 2010, a tree had fallen 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.

How to Fix A Hungry Brain

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 figure out the correct 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.

Some scientists think a more radical approach is called for. Since the triggers of obesity lie in the brain, neurosurgeons at West Virginia University Health Sciences Center are attempting to rewire 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 their normal hunger when the electrodes were switched off. Unfortunately, none lost a significant amount of weight in the study’s first year. The problem, Whiting concludes, is that there are many ways to adjust DBS. With four contact points on the electrodes, each placed half a millimeter apart and each adjustable for voltage, frequency, and pulse width, the research team has been seeking the combination of settings that most effectively rev up metabolism. So far they have found settings that work only temporarily.

“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.

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