Beyond 'You are What You Eat'

Obesity is a pandemic, and one center of the pandemic is the United States, where about 40% of adults and over 20% of adolescents ages 12-19 are obese, according to the Centers for Disease Control and Prevention. The disorder contributes to heart disease, stroke, Type 2 diabetes, certain forms of cancer and many other ailments. “It’s a crushing burden on public health and our health care system,” says Richard Mattes, distinguished professor of nutrition science and head of the Department of Public Health.

The driver for overweight and obesity is simple: regularly consuming more energy than we need to maintain a healthy body weight. However, the underlying biological mechanisms and solutions are far less clear. “We don’t know why somebody can eat one type of diet and be fine, while somebody else eats that same diet and becomes overweight,” says Kimberly Kinzig, associate professor of psychological sciences. “There’s not just a single cause of obesity; there are environmental components, biological components and genetic components.”

Purdue researchers are pursuing a broad sweep of obesity-related studies across fields ranging from nutrition science and psychology to biology and food science. One key interdisciplinary thrust is to understand eating behaviors and their results. Officially launched in 2005, the Ingestive Behavior Research Center (IBRC) located in Purdue’s Discovery Park brings together dozens of faculty members, from eight colleges at Purdue, with this goal. IBRC investigators seek to understand the mechanisms determining why, when, what and how much people eat and the effects on our health. They also seek to identify ways to improve eating behaviors, and investigate potential clinical treatments that might help those who need help.

Responding correctly to food clues

Eating is a complex activity, especially for omnivores like humans. As Mattes notes, “Every time we eat, we put different chemicals in our mouth, and our body has to determine how to handle them. It has to extract the nutrients that we need, it has to excrete toxins and other substances that we don’t want, and there’s a different mix every time.”

One focus of his lab is exploring how the sensations involved in appetite are modified both by the properties of food and beverages and by human characteristics such as levels of obesity and physical activity. “The physiological processes involved in food ingestion, digestion and nutrient metabolism are all initiated by the sensory properties of foods,” he says. “Consequently, we are particularly interested in the mechanisms and functions of oral sensory stimulation,” he says.

Some striking findings have come from his clinical research comparing the effects of consuming liquids versus solids. “Our initial thinking might be: A calorie is a calorie, so the source of energy should be of little consequence,” Mattes says. “But everything about how we handle those two food forms is quite different. Based on a number of clinical studies, our interpretation at this point is that beverages tend to add energy to the diet, rather than displacing other energy sources, so are particularly problematic for weight management.”

On a brighter side, human observational studies have long suggested rather puzzlingly that nuts, a high-fat food, actually may aid people struggling to manage their weight. Clinical trials led by Mattes and others validated that finding from observational studies. They conducted human trials that pointed to three main reasons: Nuts have a satiating effect, the energy from nuts is not efficiently absorbed, and their consistent consumption may raise energy expenditure. He and his colleagues are probing how different nuts are chewed (which might affect how much energy they deliver) and how specific types of nuts might alter how fat is stored in various places in the body (which can pose different health risks).

A sweet, sad saga

Mattes is shedding light on some previously unexpected actions of low-calorie sweeteners such as aspartame, saccharin, stevia and sucralose. “We talk about these sweeteners as if they’re all the same, but each of these compounds is a unique chemical,” he notes. “Pretty much everything about them (such as sensory properties, digestion, absorption and effects on hormones) is different. Our most recent work has been to contrast the effects of these different low-calorie sweeteners on appetite, food intake and body weight.”

The initial findings are that these sweeteners had varied effects on body weight. “Saccharin, in our hands at least so far, seems to promote increased body weight, whereas sucralose tends to be associated with weight loss,” Mattes says.

Susan Swithers, professor of psychological sciences, has demonstrated in rodents that low-calorie sweeteners actually can worsen rather than improve weight problems, because the sweeteners can interfere with the ability to deal with regular sugars. “Work in our animal models provided the first biologically plausible mechanism by which consuming artificial sweeteners could produce this counterintuitive effect,” she says.

Normally, things that taste sweet are very good predictors to expect an incoming dose of energy, she explains. Your body learns to expect that dose and to respond appropriately — for example, by releasing insulin, a hormone that helps to keep your blood sugars in a healthy range.

“But when you introduce an artificial sweetener, your body is learning that sweet taste is no longer a reliable predictor,” Swithers says. “And that becomes problematic when you get real sugar, because now your body can’t predict whether it will have the same kind of metabolic consequences.”

Long-term observational studies repeatedly have found that drinking diet sodas each day is associated with Type 2 diabetes, stroke, hypertension, cardiovascular disease and dementia. However, these studies in humans can’t clarify whether the diet sodas are at least partly responsible.

“Maybe people who are unhealthy or concerned about their weight choose to consume these sodas, but it could also be the case that these products are making it harder for people to achieve healthy outcomes,” she says. “And those aren’t mutually exclusive.”

It’s not practical to solve this problem in clinical research, one reason being that even with the best intentions, people simply don’t report their consumption accurately. But Swithers’ work with animal models has helped to clarify what is cause and what is effect. “We don’t have animals that have said, ‘I’m concerned about my weight, I’m going to switch to diet soda,’” she remarks. “If we give animals experience with artificial sweeteners, we tend to find that they gain excess weight compared to animals that are getting regular sugars, and that their ability to regulate their blood sugar levels is impaired.”

In one project, Swithers’ lab is following up on human studies that found that babies of mothers who drank diet soda while they were pregnant have an increased risk for overweight and obesity at one year of life. Swithers is leading animal studies to probe the mechanisms at work.

In the meantime, Swithers offers straightforward diet advice: “Reduce the amount of sweeteners you’re consuming, whether they have calories or not. And there’s nothing wrong with drinking water!”

Learning from gut reactions

Edward Fox, associate professor of psychological sciences, looks at how the gastrointestinal system sends messages back to the brain to help control feeding behavior. He began this work as a PhD student with Terry Powley, distinguished professor of psychological sciences, and then resumed his quest years later after returning to Purdue as faculty.

Fox’s work centers primarily on the vagus nerve, the longest nerve in the autonomic nervous system. The vagus nerve is thought to carry most of the messages back from the gastrointestinal tract that tell the brain to stop eating when you’ve had enough. “When you sit down to eat, it largely determines how much you eat,” he says. “And it turns out that obesity and almost every other disorder of eating involves a change in meal size.”

One project is to examine precisely how the vagus and other nervous systems are embedded throughout the gastrointestinal tract. “All these nerve endings tangled up in the gut are confusing, and it’s hard to decipher what’s going on,” Fox says. “But it’s really important, because that’s where nutrients are absorbed. And we don’t understand how those nutrients are tasted (so to speak) by the nerves, or how that information is signaled or processed.”

Fox and his co-workers are finishing up the first map of how nerves are distributed along the length of the small intestine. Providing these new abilities to label and map nerve terminals will help with many investigations — for example, in analyzing the roles of the microbes in the gut.

His other major area of research looks at how satiation signaling from the gut is handled in the area of the brain stem where it enters the brain. “We’re trying to identify the specific cells that are activated by those signals, and to study their connections and how they influence feeding, because we don’t really know what circuits they’re forming in the brain,” Fox says. “We need to know this in order to know what questions to ask about how the system is controlling food intake.”

A diet for brain damage

Kinzig looks at how diets with different fat compositions can influence the brain, which in turn can change overall feeding behavior.

None of the news is reassuring about the “Western diet,” high in saturated fat and sugar, which is the typical diet consumed by people in the U.S. Among its risks, the diet has been shown to impair cognitive function and alter feeding behaviors.

Her research in rodents helps to analyze the mechanisms at work. Within one day of being put on such a diet, the animals display inflammation in the brain, Kinzig says. Western diets also have been shown to cause leakiness in the blood brain barrier — the brain’s unique network of blood vessels designed to wall off toxins.

Some of her studies focus on the hippocampus, a region of the brain with many tasks in feeding. In rodents on a Western diet, “inflammation hits the hippocampus hard,” Kinzig says. The response comes in phases: inflammation soars after 10 days, subsides by 40 days, then rises again at 90 days. This response suggests that there is an early biological signal that controls inflammation for a time, but the control is not sustainable.

There’s a surprisingly similar pattern in cognitive tasks involving the hippocampus, Kinzig says. At 10 days, rodents perform worse, at 40 days they don’t, then at 90 days they do once again.

Her lab is now looking at how blood brain barrier damage can contribute to brain inflammation and contribute to cognitive decline. Pinpointing such control mechanisms eventually may prove helpful in understanding how to guard the brain against the inroads of the Western diet, she says.

Similarly, work in animals by researchers in the Swithers lab points to risks in this part of the brain. “There is strong evidence that eating a Western diet can produce damage to the hippocampus, which may normally tell you not to eat even when there are cues that tell you that food is available,” Swithers says. “So you eat more, which causes more damage. It’s a vicious cycle.”

Confronting obesity on many fronts

Major progress is being made in many fields of obesity research, but the battle will be long, researchers say.

“With current knowledge, we won’t come up with a magic bullet to treat obesity or other eating disorders, just because the feeding system in the brain is so complicated,” Fox says. “It’s been evolving since there’s been a one-celled organism that had to eat.”

“Obesity is not one disease,” Mattes adds. “Obesity is the result of many factors, and each one of us has a different combination of those factors. For some people, it’s more of an energy-expenditure problem. For others, it’s more an energy-intake problem. For some it’s a food-form problem. For others, it’s an eating-frequency problem. For others, it’s a portion-size problem.”

Eventually obesity, like cancer, will be addressed by tailoring therapies to each exact condition, Mattes predicts: “We’ll have to individualize obesity treatments to address the root cause of each person’s issue.”