NIH grant funds study on how obesity affects insulin action on skeletal muscle

MIDDLETOWN, Pa. — Through a five-year, $1.9 million grant funded by the National Institute of Diabetes and Digestive and Kidney Diseases within the National Institutes of Health, researchers led by David Williamson, assistant professor of kinesiology at Penn State Harrisburg, are studying the protein REDD1, which may play a role in how the body responds to hormones like insulin or cortisol. Understanding that role could lead to advances in the treatment of obesity, diabetes, and other insulin resistant conditions.

“Obesity has reached epidemic proportions in the U.S., permeating all demographics,” Williamson said. “Emerging reports have indicated a metabolic and nutrient role for REDD1. Basically, we are trying to understand how obesity affects insulin action on skeletal muscle. People who are obese are typically type 2 diabetic, so those individuals are less sensitive to insulin and have a propensity to have hyperglycemia. We are looking at REDD1, a mechanism that might contribute to that.”

Williamson and co-investigators Scot Kimball, professor of cellular and molecular physiology, and H.G. Wang, Lois High Berstler professor of pediatrics and pharmacology, at the Penn State College of Medicine in Hershey; and Todd Rideout, associate professor of exercise and nutrition sciences at the University at Buffalo, will examine REDD1 as a regulator of cell growth during obesity.

Williamson said that while working on another project several years ago that looked at changing protein expression between skeletal muscle from lean and obese mice, REDD1 was elevated in the obese tissue. He said that it was then that his REDD1 research began.

“It was truly serendipity. Much like anything, the question I was pursuing then opened up even more questions. While working on other related research, I began chipping away at this REDD1 finding year by year,” he said.

The researchers will begin to look at the role of REDD1 on insulin action and how the protein can improve insulin action in insulin resistant individuals, and have an impact on therapeutic approaches for obesity and other conditions presenting insulin resistance and/or skeletal muscle mass loss.

According to Williamson, because obesity is projected to increase to approximately 50 percent in the U.S. by 2030, and a major site of insulin action and glucose metabolism is skeletal muscle, maintaining normal sensitivity to growth (i.e. anabolic) stimuli, such as insulin, in skeletal muscle is paramount for overall body health.

“This research will help us understand how these stress related proteins that are regulated by stress hormones — like cortisol — can be dealt with,” he added.

Williamson said that the research doesn’t solely focus on type 2 diabetes or obesity, but insulin resistance overall.

“If you look at aged individuals, they also have high cortisol levels; they have high stress hormones; they have higher basal levels, but they don’t respond to stress like younger individuals do, so this work could have impact on other insulin resistant conditions other than obesity," said Williamson.

The team will be testing whether limiting an increase in REDD1 expression during obesity will increase skeletal muscle mass and functionality through proper regulation of cellular signaling processes.

“This work is novel because it examines the role of REDD1 on skeletal muscle growth during obesity, by dissecting a pathway that may regulate the stress regulated protein, REDD1, and examining how cell growth is altered with diet or gene manipulation of REDD1,” Williamson explained.

Stephanie Kemmerling, a senior kinesiology student, is working with Williamson on projects that complement one of the aims of the grant, where they are manipulating cellular pathways that possibly regulate REDD1.

Kemmerling said that she is excited to be doing research on an issue that is so critical to so many people.

“This research is just one step in the right direction for a lot of type 2 diabetes patients,” she said. “It is important to understand exactly what markers are causing insulin resistance in certain patients, or the population as a whole.”