Obesity researchers study thin people for clues about hunger and metabolism

By Laura Hambleton,

Maureen Michael likes food. Most days, she has three or four meals, and on occasion she eats yet another in the middle of the night. But she rarely worries about her weight, and at 5-foot-8 and 155 pounds, she looks quite trim.

“I eat anything, and I eat a lot,” the 51-year-old District resident said. “I like large portions. I have one of those metabolisms, I guess.”

Just the other day, Michael ate a salad and two large helpings of spaghetti and meatballs for dinner — after having a hearty bowl of ice cream. For breakfast the next morning, she ate two scrambled eggs, half a package of Polish sausage, English muffins and orange juice. For lunch, she consumed a 12-inch seafood sub and some Doritos, and that night’s dinner featured two pork chops, potatoes and broccoli.

That Michael’s weight remains steady even though she eats whatever she wants and does not exercise interests scientists studying the nation’s obesity epidemic. By looking at people who are near their ideal body weight, these reseachers at the National Institutes of Health’s Metabolic Clinical Research Unit in Bethesda hope to figure out what causes so many others to be overweight or uncontrollably fat.

Michael is among the one-third of American adults who are at a good weight relative to their height and build. Another third are overweight, and the rest are obese. Unlike Michael, very few people keep their weight in check without paying attention to what they eat and being conscientious about physical activity.

For years, people have been told to diet, control their appetites, use a little willpower. But more and more scientists believe the obesity epidemic has been triggered by a combination beyond an individual’s control: genes, and how they interact with an environment of abundant, tasty, inexpensive and hard-to-resist food.

Each person’s unique genetic makeup, these experts think, may affect what he craves, how much he craves and how his body uses fat and burns calories.

“We are hard-wired to be a bit more hungry than we need to, because until very recently — in evolutionary terms — the vast majority of our fellow humans had no idea whether the next meal would be available or not,” said Francesco S. Celi, a clinical investigator at the NIH research unit.

Yet for some people, there is a profound imbalance between what they eat and the amount of energy they expend. Most of these people become obese as a result, but some, like Michael, don’t.

“Some are more sensitive” to that imbalance, said Rudolph Leibel, a diabetes researcher at New York’s Columbia University who has been studying the biochemistry and genetics of obesity for 25 years. “That’s the genetics.”

“There are people in the population who are skinnier or more slender with a different genetic response to the environment,” he said. That is why “just yelling at people and telling them it is sinful or gluttony is not a particular fruitful way to deal with the problem. It’s not very effective to insinuate that someone has moral failings when a behavior is involved.”

To try to unravel the complexity of all this, researchers at an NIH diabetes and obesity lab in Phoenix have begun to incorporate thin people into their studies. Why “some [people] tend to overeat more than they need more consistently and why this occurs is clearly complex and involves levels of behavior that we are just beginning to understand,” said Jonathan Krakoff, an endocrinologist at the lab.

Krakoff and his colleagues are recruiting for a study in which thin people will consume about 4,000 calories in a 24-hour period, about twice the amount an average healthy person needs in a day.

Before participants engage in the overeating part of the study, researchers will measure their body fat and will conduct a test to make sure they don’t have diabetes or impaired glucose tolerance. Then, scientists will count how many calories the participants burn in a day while they’re studied. This measurement is done in a respiratory chamber where the amount of oxygen taken in and carbon dioxide expelled is monitored, revealing the number of calories burned.

“Some people might be able to burn off more excess calories as heat when they overeat, so they are the people more likely to be thin,” said Marie Thearle, a staff clinician involved in the study. “We are also asking our volunteers to come back for follow-up visits once a year for up to seven years to see if any of the energy expenditure measurements with overeating during the baseline study visit predict who gains weight over time and who does not.”

Thearle hopes to look deeper still into how different bodies use different nutrients, such as carbohydrates, fat and protein, and if food choices matter. “We measure whether the participant’s body prefers to use carbohydrates or fat for fuel, and then we further break this down to see how many calories are being used from carbohydrates, fat and protein, respectively.”

Thearle says the researchers hope to find out whether food choices matter. “Once you have met the needs of your body, does it matter what else you consume?” she said. “There’s the popular myth that people don’t gain weight because they have a high metabolism; we want to see if that is true. We will be looking at hormones and brown fat. We don’t think the answer is differences in metabolism.” Brown fat is the “good” fat that scientists say helps burn calories and white fat, or what we think of as regular fat.

A second study at the Phoenix lab, which will involve both slim and obese participants, is more long-range. During a six-week period, the thin people will be fed meals containing 150 percent of their weight-maintaining needs. Some will get a normal amount of protein; for others, the diet will be very low in protein. Obese people will be underfed by “50 percent of their weight-maintaining needs,” said Susanne Votruba, a research nutritionist at the lab.

Researchers will analyze every bit of what comes in and out of these participants. “For the long-term study, we measure output (urine and stool) and input (food) . . . to determine the exact calories that are going in and out,” Vortuba wrote in an e-mail.

Vortuba hopes to figure out who among the thin volunteers gains more weight over time, and why, and who among the fatter volunteers loses more weight, and why.

In Bethesda, Celi and another investigator, Kong Chen, are taking a slightly different approach. Since humans spend so much time at rest and since “obesity is an imbalance between energy intake and energy expenditure,” Celi said, he and Chen are testing what happens to a person’s output of energy, stress hormones and thyroid hormone levels when his or her body gets cold.

Some studies suggest that colder temperatures help stimulate brown fat to burn more calories. Brown fat, which runs along our neck, shoulders and spine in small amounts, is like muscle tissue in that it burns calories and helps keep the body’s internal temperature stable. Only recently have scientists discovered that brown fat persists in humans beyond infancy.

They have also found that lean people tend to have more brown fat than obese people.

If temperatures can influence brown fat so that the body expends more energy, people with a lot of brown fat may find it easier to lose or maintain their weight, Celi and Chen believe. If that is the case, then “instead of working on hunger, which is deep-seated in the brain,” Celi said, “we are working on one tissue [brown fat] that has been proposed as the holy grail of the [human metabolic] system. We bypass the brain.”

Michael is one of 24 lean recruits in a preliminary experiment run by Celi and Chen. She spent two 12-hour overnights in a specialized room with precise temperature and airflow controls. During each session inside the chamber, she ate a diet of 55 percent carbohydrates, 35 percent fat and 15 to 20 percent protein — just enough, the scientists calculated, for her to maintain her weight — while they held the room temperature at 75 degrees for one session and 68 degrees for the other.

All the while, they measured her oxygen and carbon dioxide output. They calculated her body mass. She spent 10 minutes in an oval-shape, space-age-looking machine called a Bod-Pod, which computed the weight and volume of her fat composition. She swallowed a pill containing a sensor that traced her internal temperature, while patches placed on her skin gauged her external temperature. Her heart was constantly assessed, and every 30 minutes small amounts of fluids were collected from fat tissue around her belly to evaluate her metabolism. Blood and urine samples were also taken.

Another participant, Chris Nathasingh — 31 years old, 5-11 and 170 pounds — spent his 68-degree night with only a thin blanket to supplement his pajamas. He shivered and jumped in and out of bed to keep warm.

The next morning, he was exhausted but not very hungry. The second night, the temperature was adjusted to 75 degrees, and Nathasingh slept well. “I would not say that I was hungry or hungrier [after the second night], but I definitely could not wait to eat,” he said. “Where sleep deprivation after the cold night made me only focus on sleep, the absence of such deprivation after the warm night made me focus on the next best thing: food.”

Celi and Chen are optimistic about some early findings in the trial. The participants’ energy expenditures went up when the room temperature was lowered. They plan to conduct a larger study, involving 180 volunteers, both lean and overweight.

Michael, who was a swimmer, dancer and gymnast as a girl, and who was skinnier than her girlhood friends, keeps her home at about 72 degrees in the winter (a bit warmer than she likes, but her elderly mother likes it warm) and about 70 degrees in the summer. Her weight is a little higher than she wants, but she doesn’t think about dieting. Instead, she might try some exercise.

“I need to,” she said. “I am getting older. I have slacked off as an adult. I can tell the difference.”

Hambleton is a writer and documentary filmmaker.