Would a rat risk dying just to satisfy its desire for chocolate?

I recently found out. In my laboratory, we gave rats unlimited access to their standard fare as well as to a mini cafeteria full of appetizing, high-calorie foods: sausage, cheesecake, chocolate. The rats decreased their intake of the healthy but bland items and switched to eating the cafeteria food almost exclusively. They gained weight. They became obese.

We then warned the rats as they were eating—by flashing a light—that they would receive a nasty foot shock. Rats eating the bland chow would quickly stop and scramble away, but time and again the obese rats continued to devour the rich food, ignoring the warning they had been trained to fear. Their hedonic desire overruled their basic sense of self-preservation.

Our finding mirrored a previous trial by Barry Everitt of the University of Cambridge—only his rats were hooked on cocaine.

So are the fat rats addicted to food? An inability to suppress a behavior, despite the negative consequences, is common in addiction. Scientists are finding similar compulsiveness in certain people. Almost all obese individuals say they want to consume less, yet they continue to overeat even though they know that doing so can have shockingly negative health or social consequences. Studies show that overeating juices up the reward systems in our brain—so much so in some people that it overpowers the brain's ability to tell them to stop eating when they have had enough. As with alcoholics and drug addicts, the more they eat, the more they want. Whether or not overeating is technically an addiction, if it stimulates the same brain circuits as drug use, in the same way, then medications that dial down the reward system could help obese people to eat less.

Suspicious Hormones
Until the early 1990s, society viewed obesity solely as a behavioral disorder: overweight individuals lacked willpower and self-control. Since then, the view has changed dramatically, in the scientific community at least.

The first change in opinion arose from pioneering work by Douglas Coleman of the Jackson Laboratory in Bar Harbor, Me., and by Jeffrey Friedman of the Rockefeller University. Experiments with two strains of mice, both genetically prone to obesity and diabetes, determined what drove the mice to overeat. The researchers discovered that one strain had a genetic defect in fat cells that secrete a hormone called leptin. Mice, like humans, normally secrete leptin after a meal to suppress appetite and prevent overeating. The obese mice had a leptin deficiency—and an insatiable appetite. Researchers later found that obesity in the second strain of mice was caused by a genetic defect in their ability to respond to leptin and regulate its actions. The findings seemed to make it clear that hormones regulate appetite and therefore body weight. A hormonal imbalance could lead to overeating; indeed, obesity runs rampant in certain human families that have a genetic deficiency in leptin.

Two observations suggest that viewing obesity as a hormone disorder is too simplistic, however. First, only a small number of obese people in the U.S. and elsewhere have a genetic deficiency in appetite-related hormones. Second, we would expect blood tests of obese people to show either a lower level of hormones that suppress appetite or a higher level of hormones that increase appetite. Yet the reverse is true. Obese individuals generally have a paradoxically high level of appetite-suppressing hormones, including leptin and insulin.

This is where the concept of food addiction comes into play. Appetite-controlling hormones affect certain pathways of neurons—feeding circuits—in the hypothalamus. They also affect systems in the brain that control feelings of reward, which makes perfect sense. If you have not eaten for many hours, you will spend a great deal of time, effort and money to obtain food—and it will taste very good! As the old adage says, “Hunger is the best sauce.”

During periods of hunger, hormones heighten the reactivity of food-related reward circuits in the brain, particularly in the striatum. The striatum contains high concentrations of endorphins—chemicals that enhance feelings of pleasure and reward.

As you eat, your stomach and gut release appetite-suppressing hormones that decrease pleasure signals that are triggered by the striatum and other components of the reward system. This process makes food seem less attractive, and you may switch your activity away from eating and toward other pursuits. Appetite-regulating hormones control feeding, in part by modulating the pleasurable experience of consuming a meal.

Yet some modern, appetizing foods—dense in fat and sugar and often visually appealing—affect reward systems strongly enough to override the appetite-suppressing hormones, thus prompting us to eat. These foods activate our reward circuits more powerfully than leptin's ability to shut them down. All of us have experienced this effect: you have just finished a big dinner and could not possibly eat another bite. Yet when the chocolate cake appears, you can miraculously “find room” for one last morsel—one that happens to be the most calorie-laden of the day.

Therein lies the rub. We have evolved an efficient brain system to help maintain a healthy and consistent body weight by signaling when it is time to eat and when it is time to stop. But highly appetizing foods can often override these signals and drive weight gain.

Our body responds to the override by elevating the blood levels of appetite-suppressing hormones such as leptin and insulin higher and higher as body weight increases, yet the hormones become progressively less effective as the body develops tolerance to their actions. Moreover, brain-imaging studies by researchers at Brookhaven National Laboratory and the Oregon Research Institute show that the brain's reward systems in overweight individuals respond weakly to food, even to junk food. These muffled reward circuits depress mood. How does an individual overcome this funk? By eating more delectable food to gain a temporary boost, thereby perpetuating the cycle. Obese individuals may overeat just to experience the same degree of pleasure that lean individuals enjoy from less food.

Obesity, it seems, is not caused by a lack of willpower. And it is not always caused by an imbalance in hormones. In some cases at least, obesity may be caused by hedonic overeating that hijacks the brain's reward networks. Like addictive drugs, overeating creates a feedback loop in the brain's reward centers—the more you consume, the more you crave, and the harder it is for you to satisfy that craving.

But does that make hedonic eating an addiction?

Tolerance and Relapse
Drugs of abuse, such as morphine, stimulate the brain's reward systems the way food does. Yet the similarities do not end there. When morphine is injected into the striatum of rats, it triggers bingelike overeating, even in rats that have been fed to satiety. This response shows that morphine and other opiates mimic the effects of neurotransmitters (brain chemicals) such as endorphins that are naturally produced in the brain to stimulate feeding behaviors.

We might expect, then, that drugs that block the action of endorphins could reduce hedonic overeating. Recent studies have shown that endorphin blockers do lessen the activation of reward circuits in humans and rodents that are presented with appetizing food—the subjects eat less. The blockers can also reduce heroin, alcohol and cocaine use in human drug addicts, supporting the idea that common mechanisms regulate hedonic overeating and addictive drug use. Strikingly, rats that binge on food every day display behaviors that closely resemble withdrawal, a symptom of drug addiction, after they are treated with endorphin blockers. This behavior raises the remarkable notion that hedonic overeating can induce a drug-dependence-like state.

These discoveries add credence to the idea that overeating in some circumstances may share core features of drug addiction. We see the same similarities with another basic neurotransmitter: dopamine. All known addictive drugs lead to the release of dopamine into the striatum. Dopamine is central to motivation, spurring people to seek the drug. Most experts maintain that this action drives the development of addiction, although the precise mechanisms are hotly debated. It turns out that appetizing food also stimulates the release of dopamine into the striatum, motivating people to focus on obtaining and consuming food. Imaging studies reveal that the striatum of obese individuals shows low levels of a receptor that responds to dopamine, termed the dopamine D2 receptor (D2R). The same holds true for those suffering from alcoholism or from opiate, cocaine or methamphetamine addiction.

We now also know that people who are born with reduced levels of D2R are at greater genetic risk of developing obesity and drug addiction. The condition results in lower levels of activity in the brain's reward systems, suggesting that these individuals may overeat just to obtain the same level of pleasure from food as those who do not have D2R deficits. These people also tend to have trouble learning to avoid actions that have negative consequences; brain systems involved in suppressing risky yet rewarding behaviors, such as consuming high-calorie food or using drugs, may not work as effectively.

Our lab study of rats backs up this idea. The obese rats that ate the cafeteria food regardless of warnings about being shocked had reduced levels of D2R in their striatum. Our study and others demonstrate that drug use in addicted rats and hedonic eating in overweight rats persist even when the animals face negative consequences. Many obese individuals struggle so badly with their poor food choices that they will voluntarily undergo potentially dangerous procedures, such as gastric bypass surgery, to help them control their eating. Yet very often they will relapse to overeating and gain weight.

This cycle of engaging in a bad habit that gives short-term pleasure, then attempting to abstain from it and eventually relapsing, sounds disturbingly like drug addiction. Given the latest research, it seems that obesity is caused by an overpowering motivation to satisfy the reward centers—the pleasure centers—of the brain. The hormonal and metabolic disturbances in obese individuals may be a consequence of weight gain rather than a cause.

New Treatments Possible
The similarities between obesity and addiction have led certain experts to say that the two conditions should be treated in the same manner. Some of them recommended that obesity be included in the most recent update to the Diagnostic and Statistical Manual of Mental Disorders—the bible of psychiatry that provides guidelines for diagnosing mental illnesses, known as the DSM-5. This proposal sparked lively debate among neuroscientists and psychiatrists, but arbiters for the DSM-5 ultimately dropped the idea, largely to avoid labeling obese people, in essence, as mentally ill.

Caution may have been warranted because despite the parallels, obesity and addiction differ in important ways. For example, if food is addictive, then surely it must contain some unique component that drives the addiction—the nicotine of junk food, if you will. Work by Nicole Avena of the University of Florida, the late Bartley Hoebel of Princeton University and others lends some credence to the idea that particular fats or sugars may be responsible. A small study by David Ludwig of Boston Children's Hospital suggests that highly processed, quickly digested carbohydrates could trigger cravings. But research overall indicates that no one ingredient stokes addictionlike behaviors. Rather the combination of fats and sugars, together with calorie content, seems to maximize food's “hedonic impact.”

Other experts, including Hisham Ziauddeen, I. Sadaf Farooqi and Paul C. Fletcher of the University of Cambridge, do not think that tolerance and withdrawal occur in obese people the way they do in drug addicts. They argue that obesity and drug addiction are fundamentally different. This view is debatable, however. If obese individuals must eat more and more to overcome reduced activation of reward networks in the brain, that sounds a lot like tolerance. And weight loss can trigger negative mood and depression, much like that experienced by former addicts who try to practice abstinence, suggesting that withdrawal may be in effect.

Other experts have argued that the entire notion of food addiction is preposterous because we are all, in a sense, addicted to food. If we were not, we would not survive.

The difference in obesity, I would suggest, is that modern high-calorie foods can overwhelm our biological feedback networks in a way that other foods cannot. During millions of years of evolution, the major concern of humans was not suppressing appetite but hunting, collecting or growing enough food to persist during lean times. Perhaps our feeding circuits are better at motivating food intake when we are hungry than they are at suppressing food intake when we are full. It is easy to imagine that the brain would regard overeating of high-calorie food as tremendously beneficial if it is unclear when food will again be available. Perhaps this behavior is no longer adaptive and could even be counterproductive in a world where food is bountiful.

The scientists who argue against an addiction model of obesity make reasonable points, and I also fear that the term “addiction” comes loaded with unhelpful preconceptions. Still, compulsive eating and compulsive drug use seem to share obvious features, most notably an inability to control consumption. It is up to scientists to determine if these similarities are superficial or stem from common, underlying alterations in the brain. More important will be determining whether the addiction model is useful. Unless it helps us design new treatment approaches, the debate is simply an academic exercise.

For an addiction model to have value, it should make accurate predictions about treatment options, including new medications. One example comes from Arena Pharmaceuticals, which recently obtained approval from the U.S. Food and Drug Administration to market a drug called Belviq for weight loss in obese or overweight adults. The drug stimulates a brain protein called the serotonin 2C receptor, which reduces the desire to consume nicotine in lab rats.

Another drug is rimonabant, which had been approved in Europe to help curb appetite in obese individuals. The drug exploits the well-known property of cannabis to increase desire for food—the so-called munchies. Cannabis activates a brain protein called the cannabinoid receptor 1, so researchers reasoned that inhibiting that receptor would decrease desire for food. Rimonabant does exactly that. A notable side effect is its ability to decrease tobacco users' desire to smoke. In rats, the drug also decreases the desire to use alcohol, opiates and stimulants such as cocaine.

As with all potentially therapeutic drugs, however, caution is required. Rimonabant has triggered depression and thoughts of suicide in some individuals. This finding led European authorities to suspend its use and prompted U.S. officials to not approve it. Why depression emerged is still unclear. Thus, although an addiction model of obesity could yield unexpected treatments, those modalities must be thoroughly scrutinized.

Before scientists can declare that overeating is or is not an addiction, they will have to identify precisely which networks and cellular adaptations in the brain drive compulsive drug use and then determine if the same mechanisms also motivate compulsive food intake. It is possible, even likely, that addiction networks for cocaine and for food operate in different parts of the brain yet use similar mechanisms. Scientists will also have to determine if common genetic variations, such as those that affect D2R, contribute to drug addiction and obesity. Identifying such genes may reveal new targets for medications to treat both disorders.

Even if scientists prove that obesity can stem from an addiction to food, and we find that antiaddiction medications can help people lose weight, obese individuals will have to struggle with one factor that seems now to be endemic in America: they will probably be surrounded by overweight family members, friends and co-workers who are still overeating, putting them in the same difficult environment they were in before. As we know from recovering drug addicts and alcoholics, environmental cues are a major cause of craving and relapse. Western society, saturated in fat and temptation, will make it hard for any obese person to quit.