Keeping Colorado lean

As the leanest state in the nation, Colorado might seem an unlikely spot for an international hub of obesity research. Jim Hill sees it differently.

“We are in a great position to conduct research on what keeps us the leanest state and how we can stay that way,” said Hill, Ph.D., director of the Colorado Nutrition Obesity Research Center at the University of Colorado Anschutz Medical Center. “We have a broad, deep, and comprehensive research group here that can address this issue in a way most places can’t.”

With more than 120 interdisciplinary researchers receiving roughly $30 million annually to study obesity and related diseases, CU is quickly gaining a reputation as a leading source of “bleeding-edge” science aimed at turning the obesity epidemic around. In the past year, researchers there have: identified a gene key in influencing how the body metabolizes fat; discovered that sleep is more important than previously believed in regulating appetite; and begun to study the role that bacteria in the gut plays in regulating weight. Meanwhile, others are exploring how a predisposition toward obesity begins in the womb — and what moms-to-be can do to break the cycle.

“We have come to realize that obesity is a disease as opposed to simply a failure to control a lifestyle,” said CU obesity researcher James McManaman, Ph.D., who studies proteins that regulate metabolism. “It is far more complex than we had imagined.”

In April, 2012, CU also opened the $34 million, 98,000-square-foot Anschutz Health and Wellness Center to provide cutting-edge weight loss and sports-performance programs to the public, and facilitate human studies on what diet, exercise, and mental strategies work to help people lose weight and keep it off. (The center will be the site of ABC’s reality TV show Extreme Weight loss this year).

At a time when 36 percent of the U.S. population and 20 percent of Coloradans are obese, Hill believes that Colorado — using home-grown research — could soon set another example: by becoming the first state to see its obesity rates go down.

Here’s a look at some research priorities:

Deleting the fat gene

In March 2013, McManaman and his colleagues published a groundbreaking federally funded paper that found that when mice were bred to lack a gene called Plin2, they demonstrated a remarkable resistance to obesity, even when tempted with a high-fat diet. When given feed containing 60 percent fat, they gained less weight, ate less food, and exerted more energy over a 12-week period than peers who had the gene. They also showed fewer signs of fatty liver disease (a dangerous accumulation of fat in the liver which can set the stage for obesity).

The fat they did have on their bodies was healthier, quick-burning “brown fat”, rather than “white fat” which tends to stick around and accumulate. McManaman is now working to find out just what Plin2 does in the liver and intestines to regulate appetite and metabolism. Ultimately, he believes a drug could be developed to silence the gene in humans, providing obese people for whom diet and lifestyle changes have failed with another tool.
“Once you become obese, your body starts to adapt to try to defend that higher weight,” he said. “Their metabolism has changed so much, they might benefit from medication”

Breaking the cycle

Studies have long shown that overweight moms tend to have overweight kids. Research by Jacob Friedman, Ph.D., a professor of pediatrics, biochemistry and molecular genetics at CU, suggests that predisposition begins in the womb, and is heavily influenced by what mom eats during pregnancy.

One recent study in primates found that those who ate a high-calorie, high-fat (35 percent) diet during pregnancy (regardless of whether they were overweight) produced fetuses with fatty-liver disease and babies with more fat cells. When moms-to-be eat too many calories and too much fat, it may also impair mitochondria (the fuel-burning engines within muscle tissue), promote inflammation, and cause cell-damaging oxidative stress in an unborn child or infant, potentially setting them up for a lifetime of weight problems, Friedman said.

Diabetic and overweight moms have long been warned to cut back on sugar during pregnancy, but Friedman fears that is leading some to replace it with fat, which comes with its own consequences.

He’s now conducting a study looking at whether moms on a low-fat, high-complex carbohydrate diet have fewer fat, metabolically healthier babies.

He and other CU researchers are also looking at how the microbiome, or gut bacteria, of an obese pregnant mom differs from that of a normal-weight mom, and what happens to baby when that microbiome is transferred to them via the birth canal and breast milk.

Ultimately, he hopes his research can lead to better science-based diet advice to pregnant moms hoping to set their babies up for a life of healthy weight. For babies who have already been born to obese mothers, he’s exploring the use of probiotics (via mom’s breast milk) to normalize their gut bacteria, or antioxidant supplements to help repair damage from oxidative stress.

“Ultimately, we want to look at how maternal obesity impacts all metabolic systems and whether, if we switch them to a healthy diet, we can reverse some of these changes.”

Changing lifestyle

New drugs and peri-natal interventions aside, CU researchers are also studying what lifestyle changes — from sleep habits and mental strategies to diet and exercise — work to help keep weight off.

In March, Kenneth Wright, director of CU’s Sleep and Chronobiology Laboratory, published a study that observed 16 young, lean, healthy adults who lived at the University of Colorado Hospital Sleep Suite, where their sleep was controlled and meals and snacks were provided. Those who slept just five hours per night for five days ended up eating 6 percent more calories than those who got nine hours of sleep and tended to eat small breakfasts but binge on late-night snacks. They gained 2 pounds.

“When people are sleep-restricted our findings show they eat during their biological night time when internal physiology is not designed to be taking in food,” Wright said.

In the coming year, at the Anschutz Health and Wellness Center, Hill said he hopes to explore the critical role that exercise plays in helping people keep weight off once they have lost it.

Already, research from CU and elsewhere suggests that exercise builds more and larger fuel-burning mitochondria in the muscles, boosts insulin sensitivity, and helps the body switch more easily between different fuel sources (fat, carbohydrates and protein) without storing them as fat.

“You absolutely have to exercise to fix your metabolism and get it functioning normally again,” Hill said. “Otherwise, if you take the weight off with diet alone, you’ll just regain it.”

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