Web edition: September 21, 2012
Print edition: October 6, 2012; Vol.182 #7 (p. 24)
Most people would never equate downing a well-dressed salad or a fried chicken thigh with toking a joint of marijuana. But to Joseph Hibbeln of the National Institutes of Health, the comparison isn’t a big stretch.
New animal experiments by Hibbeln and his colleagues have recently shown that the body uses a major constituent in most vegetable oils to make its own versions of the psychoactive ingredient in marijuana. Called endocannabinoids, these natural compounds play a role in heightening appetite. So overproducing them unnecessarily boosts hunger, similarly to how pot triggers the munchies (SN: 6/19/10, p. 16).
If what happens in people mirrors what happens in animals, then the prevalence of soybean oil, corn oil and other polyunsaturated vegetable oils in today’s Western diet means your body is “dumping out a lot of these marijuana-like molecules into your brain,” explains Hibbeln, a nutritional neuroscientist. “You’re chronically a little bit stoned.”
Vegetable oil’s link to endocannabinoids is just one example of newfound and surprising ways that foods can confuse calorie-sensing networks and foster obesity — in some cases by damaging the brain. Especially troubling: Excess body weight itself can exaggerate the risk of the brain telling a well-fueled body that it is running on empty.
By understanding what messes with the body’s satiety meters and why, scientists hope to identify tactics for reducing a diner’s likelihood of becoming another statistic in the obesity epidemic.
Energy in the balance
Responsibility for monitoring calorie input and energy output falls to the brain. And the job is not easy, says endocrinologist Michael Schwartz, director of the University of Washington’s Diabetes and Obesity Center of Excellence in Seattle.
To maintain a constant weight, a 160-pound man would need to consume “about 1 million calories over the course of a year,” Schwartz explains — “and expend almost exactly that same million calories.” Only by integrating hosts of chemical signals day and night can the brain manage this energy-budgeting feat, which it has done quite well for most people throughout most of history.
Though scientists once thought the body controlled appetite through a process of error correction, they now know that the brain doesn’t wait for mistakes to occur before sending signals that alter everything from blood pressure and breathing rates to food intake. It instead predicts upcoming needs by analyzing outputs from sensors assessing internal and external conditions. This anticipatory process is known as allostasis.
People tend to become consciously aware of this complex balancing act only when the brain triggers the release of hormones that elicit sensations of hunger, thirst or some overwhelming sense of fullness. But allostasis may occasionally stumble in the context of the current food environment.
Throughout much of human history, hunger would have dominated; chronic famine was the rule. So evolution has programmed the brain to prompt the body to pig out on energy-dense foods, especially fats, whenever they become available, says Daniele Piomelli of the University of California, Irvine. By gorging on fat during brief dietary bonanzas, people could store enough energy to get through the next caloric dry spell.
Today, with 24/7 access to food, a biological drive to eat high-calorie fare is rapidly evolving into a health liability. Globally, more than one in five adults are overweight, with more than a third of them obese. And in some countries, including the United States, one in six children over age 2 are also obese.
The brain’s faulty anticipation of energy needs, as well as other forms of neural confusion, may be fostering an unconscious urge to overeat.
Chewing the fat
Piomelli can attest to that. Last year, his team showed that diets high in vegetable oils messed with allostasis. These oils triggered overeating in animals by turning on production of hunger-promoting endocannabinoids (SN Online: 7/8/11). In an upcoming issue of Obesity, Hibbeln’s team now blames this trickery on the linoleic acid found in that oil.
The central role of endocannabinoids in the nervous system’s regulation of food intake has been known for at least a decade, Hibbeln says. When endocannabinoids bind to cellular structures known as receptors, brain tissues release dopamine, a messenger molecule that elicits a pleasant feeling. Until this reward system turns off, an urge to eat persists (SN: 6/19/10, p. 16).
When a person downs too much linoleic acid, it is as if the reward-seeking switch in the brain gets stuck in the “on” position. The impact — at least in Hibbeln’s mouse study — is visible to the naked eye.
Some of the animals in the study chowed down on a diet that derived 1 percent of its calories from linoleic acid, a proportion consistent with what Americans typically ate around 1900. Animals in a second group ate food in which linoleic acid supplied 8 percent of all calories, an amount in line with what’s found in a more modern U.S. diet. Even though both groups received the same proportion of their calories from fat and carbs, mice getting more linoleic acid gained substantially more weight.
Those mice not only ate more, but they also gained more fat for every calorie eaten, Hibbeln explains. “You and I would rather eat more and gain less weight — and that would be what we saw with rats getting 1 percent linoleic acid.”
By promoting overeating, linoleic acid may trigger other changes that further derail the brain’s ability to manage calories. Any energy the body consumes but doesn’t use gets stored as fat. Hardly deadweight, fat can recruit immune cells that can spew inflammatory molecules and foster disease (SN: 2/28/04, p. 139).
Early research had suggested that the heart and the rest of the circulatory system were the main victims of these molecules. But emerging data indicate that fat-triggered inflammation also harms the brain.
For instance, Schwartz’s group fed some normal-weight rodents standard chow for eight weeks to eight months and gave others meals with much more fat. Within a day, animals getting the fattier diet, but not the others, showed signs of inflammation in a part of the brain’s hypothalamus known as the arcuate nucleus. When nerve cells here are activated, they drive hunger. As activity dials back, animals eat less, sometimes even losing weight.
Within a week of beginning the fatty diet, rats showed biochemical evidence of ongoing cellular destruction in this brain area. Shortly afterward, the cell damage appeared to subside. Two weeks later the damage returned.
Nerve cells in the arcuate nucleus aren’t the only players in eating and satiety, Schwartz notes, “but they seem especially important in terms of processing inputs from signals in the blood that are informing the brain about how much body fat mass there is.” And not surprisingly, as brain damage progressed, the rats ate more than they needed to maintain their body weight. They ended up gaining weight, Schwartz’s team reported in the January 3 Journal of Clinical Investigation. The team saw the same effect in mice.
As the brain damage became chronic, the arcuate nucleus appeared to lose its sensitivity to hormonal cues about how much body fat exists, Schwartz says. The brain interprets a reduced signal to mean that there is not enough body fat, and thus delays any command to stop eating. “Because you get less bang for the buck when you eat, in terms of satiety,” he says, “you eat bigger meals.”
Scans of similar brain regions in people who were lean, overweight or seriously obese showed signs that this kind of brain damage may not be limited to rodents. More or less, Schwartz says, the heavier a person, the bigger the signs of cellular destruction.
Other studies have found additional signs of damage in the brains of obese people, though this work hasn’t pegged inflammation as the instigator.
In one such study, endocrinologist Marc-Andre Cornier of the University of Colorado Denver and his colleagues identified a body fat–related deactivation of the shutoff switch for a neural processing center known as the default network. Spanning several brain regions, this network normally engages only when people are not consciously thinking or focused.
Once people start to focus on a task, the network should turn off, says Cornier. But, reporting late last year in Obesity, his team found that among formerly heavy people who had dieted and were now still somewhat overweight, the default network never shut off. This was true even when the study participants hadn’t overeaten.
This network’s activity could prove a distraction, Cornier says, preventing the brain from effectively monitoring satiety cues: “We know, for instance, that the more obese you are, the more you underestimate the number of calories that you eat and the less likely you are to feel hunger and satiety.”
Related work linked obesity in teens with a reduction in the size of an area of the brain known as the orbitofrontal cortex, which plays an important role in inhibiting all types of behavior. Compared with lean teens, heavyweights showed impaired decision making, attention and monitoring of behaviors, and exhibited increased impulsivity, Antonio Convit of the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, N.Y., and colleagues reported last year in Obesity.
Excess body fat may be only a proxy for what is really behind the brain problems: inflammation, high blood pressure or prediabetic changes like poor blood sugar control. “We think that maybe the obesity and these other factors cause the damage that lowers the brakes on certain behaviors, which in turn allows kids to eat more than they should,” Convit says. “It sets up a vicious cycle.”
A not-so-sweet trend
Low-calorie foods may also reeducate the brain’s calorie-sensing machinery with lessons that might be best never learned.
Some 187 million Americans consume sugar-free foods and beverages, mostly in the form of soft drinks. Although a majority choose artificially sweetened soft drinks to keep from gaining extra pounds, such drinks may actually contribute to weight gain.
It’s something Sharon Fowler of the University of Texas Health Science Center at San Antonio and her colleagues documented in a 2008 study. They analyzed data on almost 3,700 participants of a long-running heart study. Among recruits who started with a normal weight, frequent diet-soda drinkers went on to become overweight or obese during the next seven to eight years at roughly twice the rate seen among participants who avoided diet drinks. Fowler’s group concluded that artificial sweeteners might be fueling the obesity epidemic that they had been designed to fight.
The problem may trace to the fact that diet drinks cause the brain to receive unreliable cues to a meal’s calorie count, suggest animal experiments by behavioral neuroscientist Susan Swithers of Purdue University in West Lafayette, Ind. In what amounts to real-world Pavlovian training, the brain learns to link sweet-tasting foods passing through the mouth with the subsequent release of calories in the gut. But when that dietary signal becomes untrustworthy, with sweetness sometimes indicative of incoming energy, other times not, the brain abandons sweetness as a gauge of expected calories.
By the time the brain figures out how much energy it has gotten in any given meal, animals who had downed sugary foods will have overeaten.
Mixed caloric messages from sweeteners can also mess with the hormonal milieu that normally signals when it is time to push back from the dinner table. For instance, a key satiety hormone known as GLP-1 was inappropriately low after sugary meals in rodents that had, over the course of several weeks, received erratic clues to the energy associated with sweetness.
Low GLP-1 led to elevated blood sugar, even though the animals’ production of insulin — secreted to manage blood sugar — remained normal, Swithers’ team reported July 15 in Behavioral Brain Research. If the same thing happens in people, then artificial sweeteners could prove a double whammy for overweight diabetics who often turn to the sweeteners to help control their waistlines and blood sugar.
The brain’s energy-tallying network is also vulnerable to confusion when oral fat sensors relay inconsistent signals, the Purdue group finds. A study published by the team last year in Behavioral Neuroscience linked substantial weight gain in animals to the occasional replacement of fat with olestra, a no-calorie substitute.
Fighting the fat
Together, these findings suggest that the brain, a longtime master at tracking caloric intake, can be fooled. And when that happens, Swithers observes, weight management suddenly becomes challenging. “Now we have to start counting calories, reading food labels and tracking how many steps we took today,” she says.
But for people who are overweight, a sustained, long-term exercise regime may offer unconscious benefits. Cornier and his colleagues showed that halfway into a yearlong program of supervised treadmill exercise, most of a dozen adult recruits were losing fat and weight. Although participants reported no drop in appetite, brain scans revealed that regions helping to regulate food intake were less responsive to visual images of food than before the trial began — a potential boost for dietary willpower. It’s still preliminary, Cornier says, but this exercise regime appears to help repair the default network’s faulty switch.
Benefits may also come from tweaking the endocannabinoid system. But first researchers need a better understanding of how it works.
Piomelli’s team recently reported signs that the brain’s response to fat begins in the mouth, where taste sensors shoot an immediate message to the brain that calories are coming. The brain then warns the gut. When the fat actually arrives there, confirmation returns in the form of reinforcing endocannabinoids.
That the brain receives signals both before and after fat arrives in the gut “was completely unexpected,” Piomelli says, “and makes no sense, unless this endocannabinoid system in the intestine is doing more than one thing.” He now suspects this signaling system is “not just there to make us eat more fat, but also to facilitate fat’s absorption.”
If true, he says, then this may offer new ways to intervene therapeutically, for instance with drugs that alter signals associated with fats.
Hibbeln has an even simpler and more immediate solution: Diminish the endocannabinoid signal by reducing the intake of linoleic acid or blunting its impact.
The United Soybean Board, an industry group, reports that for reasons unrelated to the recent linoleic acid findings, it is developing new soy crops that will yield an oil high in oleic acid (the prominent fatty acid in canola and olive oils) and low in saturates. One by-product of this tinkering will be a dramatic drop in the linoleic acid fraction in soybean oil from more than 50 percent to less than 5 percent.
Until the new oil arrives in stores, diners might want to switch to olive or high-oleic canola and sunflower oils, and increase their consumption of fishy omega-3 fatty acids, Hibbeln says. In his experiments, mice getting a diet high in linoleic acid proved fairly resistant to fattening up if they also had fish oil.
Unfortunately, strategies for keeping the brain’s signaling system on point offer the most promise for people who have not yet begun fattening. “The biggest problem with obesity is not that you can’t lose weight, it’s that you can’t keep lost weight from coming back,” Schwartz says. New findings suggest that once the body gains weight, the brain tends to begin vigorously defending that new weight with signaling that occurs at an unconscious level.
It’s no secret that protecting the brain from diet-induced trickery or outright damage will be challenging, Schwartz says. But identifying the culprits, whether faulty messages or damaged brain cells, may make way for solutions. “I am very optimistic that interventions to effectively prevent and treat obesity are in our future.”
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