That the United States has an obesity epidemic is hardly news. Obesity rates in the United States have tripled since 1960, and today more than 40% of American adults and 20% of children and adolescents are obese, according to the Centers for Disease Control and Prevention (CDC). In 2019, Kansas became one of 19 states in the country with an adult obesity rate of at least 35%.

Obesity, defined by the CDC as a body mass index (BMI) of 30 or higher, dramatically increases a person’s risk for heart disease, type 2 diabetes, fatty liver, kidney disease, hypertension, orthopedic problems, dementia and stroke. If that weren’t enough to sound an alarm, the pandemic certainly did as public health officials warned that obesity significantly increases a person’s risk of dying from COVID-19.

Meanwhile, obesity is poised to become the new smoking in terms of cancer prevention. Obesity is expected to surpass tobacco use as the biggest preventable cause of the disease.

It is easy to blame the obesity pandemic on Americans’ increasingly sedentary lifestyles and a diet composed of processed foods full of sugar and fat in ever-larger portion sizes. But obesity, and the other diseases it causes and exacerbates, cannot be reduced to those unnuanced factors. Genetics, biology, behavior and environmental and social determinants of health — even things like proximity to grocery stores that sell fruits and vegetables and having a safe place to exercise — also play a role in a person’s likelihood to have obesity.

“Obesity is caused by many factors, personal and environmental, and varies by individual,” said Joseph Donnelly, Ed.D., director of the Division of Physical Activity and Weight Management at KU School of Medicine. “It is very complex, and causes — such as overeating, inactivity and medication side effects — may even change over time.”

Despite advances in obesity treatment, such as bariatric surgery and new weight loss drugs, and a better understanding of some of the genetics and biology, obesity rates continue to rise nationally and in Kansas.

“Our environment — our food environment, our physical activity environment, our screen time, our jobs — is set up so that it's really hard NOT to gain weight over time,” said John Thyfault, Ph.D., director of the KU Diabetes Institute and a physiologist who studies how exercise and inactivity affect susceptibility to obesity. “For many people, obesity is not really a choice.”

Location, location, location

It is easy to think that body fat is always a bad thing, but fat is more complicated than that.

“Not all weight is the same,” noted Steven Weinman, M.D., Ph.D., director of the KU Liver Center.

As in real estate, it is all about location, location, location.

Visceral fat, which is fat deep in the abdominal area, produces hormones that can cause inflammation and is correlated with type 2 diabetes and fatty liver as well as metabolic syndrome, a range of conditions that together raise the risk of coronary heart disease, diabetes and stroke.

But not all flab is bad. Subcutaneous fat, which is under the skin, is much healthier.

“That’s why BMI is not always the best measure of whether you're healthy related to your weight,” said Weinman. “Many feel that waist circumference is a better measure of risk for obesity-related disease than BMI.”

It is also why women who are pear-shaped are protected against obesity-related disease, noted Thyfault. Fat in the thighs and hips is healthier fat than belly fat and love handles.

Moreover, fat cells are not merely inert repositories of excess calories. Fat is now regarded by many to function as an endocrine-system organ, sending hormone signals to other parts of the body. For example, the hormone leptin, which is produced in fat cells, regulates eating by producing the sensation of feeling full, which is a good thing. But people with obesity produce too much leptin and can become resistant to the hormone’s good effects. Adiponectin, another hormone made in the fat cells, improves insulin sensitivity and helps regulate glucose levels. But when a person becomes obese, adiponectin levels fall, and the result can cause diabetes and heart disease.

Thyfault stressed that people can make a big difference in their health just by making incremental changes.

“We put way too much emphasis on losing weight instead of protecting against weight gain,” Thyfault said. “The average American can gain one to two pounds every year of life. If we could stop that from occurring, we would make a lot of progress.”

Bridging divides

In October 2022, the University of Kansas Medical Center was awarded a $12 million grant from the National Institutes of Health (NIH) to launch a research center to study obesity and obesity-related diseases. The new Kansas Center for Metabolism and Obesity Research (KC-MORE) provides facilities and support for researchers who study these conditions as well as funding for junior faculty starting careers in obesity and metabolic-related science. KC-MORE is part of the NIH’s Centers of Biomedical Research Excellence (COBRE) program. Its goal is to make KU Medical Center a national hub for research to prevent and treat obesity and to understand the role of metabolic defects on diseases associated with obesity.

KC-MORE might be new, but weight and obesity have been a subject of study across the medical center for decades. Researchers and clinicians looking at obesity come from the KU Diabetes Institute, the KU Liver Center, the Division of Physical Activity and Weight Management, the Department of Cell Biology and Physiology, the KU Center for Physical Activity and Weight Management, The University of Kansas Cancer Center, the Department of Dietetics and Nutrition, the Center for Children’s Healthy Lifestyles and Nutrition and the KU Alzheimer’s Disease Research Center.

Two months after the new center was announced, the NIH awarded KU Medical Center a five-year, $1.3 million grant to provide training focused on obesity, metabolism and obesity-induced pathologies for pre-doctoral graduate students. The goal is to train scientists who bridge the divide between camps that usually don’t talk to each other.

“The link between these kinds of investigators don’t happen naturally,” said Thyfault, who, along with Weinman, is a co-principal investigator for KC-MORE. “For instance, the Liver Center team studies fatty liver but did not always interact with obesity or metabolic researchers. Obesity researchers know that more body fat influences how much fat is stored in the liver, but they may not understand liver metabolism or how modifying body weight and reducing the presence of body fat can change the prognosis of liver disease.”

One of the missions of KC-MORE is to change that dynamic, to move away from a siloed approach. It is in the spaces between disciplines, Thyfault said, that important scientific discoveries are often made.

Accelerating cancer progression

Michael VanSaun, Ph.D.

An understanding of fat’s role in the body has been critical to the research of Michael VanSaun, Ph.D., assistant professor of cancer biology. Obesity has been linked to 13 different kinds of cancer. VanSaun’s lab is studying how and why.

Cancer is caused by damaged genes that produce damaged proteins, which in turn cause cells to grow out of control and form tumors. VanSaun says it isn’t known for certain if obesity can cause the initial gene damage that sets that process in motion, but obesity seems to drive cancer’s progression.

“Think of it like this,” VanSaun said. “You have a car, and it's not going. You get the first mutation, and you push the gas down a little bit, so the cell is now moving and growing, right? And then you develop obesity, which really hammers down on the accelerator. Now your cells are aggressively proliferating.”

VanSaun’s lab has been collecting fat cells and putting them with cancer cells in a Petri dish. They have found that while lean fat tissue effects the growth of cancer cells, obese fat tissue is far more potent. He has also discovered that the fat tells the cancer cells to start secreting factors that then cause immune-system cells to be suppressed. This interaction means that if an obese cancer patient wanted to try an immunotherapy-based cancer treatment, it might not work.

Here again, location matters. In his research in pancreatic cancer, VanSaun has found that the fat located right around the diseased pancreas is especially potent.

“We think that the fat is what helps the tumor cells to start streaming out of their normal site and into surrounding tissues, which could lead to metastasis,” he said.

VanSaun’s lab is looking for drugs to stop these interactions with the hope of creating vulnerabilities in or starving cancer cells, particularly for pancreatic cancer, which is one of the deadliest forms of the disease.

Fueling chronic pain

Julie hristianson, Ph.D.

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Julie Christianson, Ph.D., professor and vice chair in the Department of Cell Biology and Physiology, is interested in how early-life stress affects how people perceive and process pain signals. In research she conducted using a mouse model, she noticed that mice who experienced early-life stress had more fat mass and weighed more.

“Having that early-life stress does make them more susceptible to developing obesity and to having higher blood glucose levels,” she said. “So they develop what looks like metabolic syndrome more easily.”

Meanwhile, early-life stress also led to evidence of pain disorders, often earlier than the increase in body weight. Christianson suspects that the pain and weight gain are arising from similar underlying biological mechanisms.

“We know there are changes in the brain, gene changes in the hippocampus, caused by stress.  These early changes in the brain are also changing things downstream,” Christianson said. “I believe that the pain and the obesity are on their own trajectories in the beginning, but then they begin feeding into each other. If you have pain, you won’t want to exercise as much. And if you have excess weight, that can cause pain itself through inflammation.”

Christianson’s lab is looking at how early-life stress exposure affects life after weight loss. So far, they have more discouraging news: overweight mice who had stress early in their lives and then lose 20% of their body weight end up regaining more weight than mice who did not experience stress.

“Now we need to figure out how this relates to humans in terms of socio-economic disparities,” said Christianson. “All these early-life stressors are more prevalent in underserved, disadvantaged communities.”

Changing behavior early on

With one in three kids in the United States overweight, obesity is the most prevalent chronic condition for children. Heavy children are far more likely to be heavy adults, and this generation is the first predicted in more than two centuries to have shorter lifespans than their parents. Early in 2023, the American Academy of Pediatrics released new guidelines for treating children who are overweight. In addition to prescribing weight loss drugs in certain cases, the guidelines recommend health behavior and lifestyle treatment programs.

“The important characteristics of this treatment are that it's family-based, that it's multicomponent, that it includes a focus on nutrition, physical activity and other behavior changes,” said Sarah Hampl, M.D., pediatrician at Children’s Mercy and clinical assistant professor of pediatrics at KU School of Medicine, who chaired the committee that produced the new guidelines.

Ann M. Davis, Ph.D., professor of pediatrics at KU School of Medicine, serves as director of the Center for Children's Healthy Lifestyles and Nutrition at KU Medical Center and Children's Mercy. Through the center, Davis has been leading an NIH-funded project called “iAmHealthy” that partners with Kansas elementary schools to recruit families interested in living healthier lives. The program targets rural areas, which have higher rates of obesity and less access to programs such as this one.  

Children and their parents use a mobile health app to participate (they originally met in person at the school, and Davis joined virtually from Kansas City). For six months, they learn to make changes to their physical activity, nutrition and parenting.  

“We looked at the data, and when parents went on walks and ate more fruits and vegetables, got rid of the soda pop and did all the things we recommend, their kids benefited more from the program,” said Davis.

Since launching in 2006, the iAmHealthy intervention has proved successful. The average BMI of children receiving the intervention decreased significantly more than that of children who saw a physician to address their weight.

The whole spectrum

To fight the obesity epidemic and its related diseases, researchers and clinicians at KU Medical Center know they need to work together to tackle the problem from a number of angles. It is a massive, multifaceted problem with no easy solution.

“We are trying to cover this whole spectrum, from people who are more or less healthy but need to lose weight to remain healthy, to people who have obesity-related diseases,” said Weinman. “We are concerned about obesity because we want people to be healthier. And that's really the goal.”