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A University of Nebraska Medical Center research study could provide new clues on cell metabolism including how energy is regulated and used. The findings, published as the cover story in the latest issue of Cell Metabolism, show that mice are obese and insulin resistant when they lack a gene that interacts with, and controls, enzymes that regulate a cell’s energy level.
“What is interesting and different about this mouse is that it eats slightly, but significantly less than its normal brothers and sisters and is more active, but is fat,” said Rob Lewis, Ph.D., professor in the Eppley Institute at UNMC. “It’s not unlike the person who diets, but has trouble losing weight.”
The genetically modified mouse model developed in Dr. Lewis’s laboratory lacks a protein called Kinase Suppressor of Ras 2 (KSR2). The study shows that, in mice, KSR2 interacts and controls the activity of AMPK, an enzyme that promotes energy generation, while preventing energy storage. When KSR2 is disrupted, AMPK function is impaired, which Dr. Lewis believes contributes to the obesity of the adult mice.
“The data show that mice deficient in KSR2 are highly efficient in conserving energy,” Dr. Lewis said. “This study reveals an unexpected role for KSR2 in AMPK-mediated regulation of energy metabolism. The insulin resistance appears to be secondary to obesity and similar to what physicians observe in some obese humans.”
He said there is no data to suggest that KSR2 affects insulin resistance in humans, although a commonly prescribed drug for treating diabetes is thought to indirectly activate AMPK to promote glucose uptake.
Dr. Lewis will continue to explore the essential contribution of KSR proteins to metabolism in obesity, insulin action and cancer.
“We know that cancer cells commonly change the way they metabolize glucose,” he said. “Recent studies have shown that this shift in metabolism is critical to tumor development and survival. Our preliminary studies suggest that KSR2 and a related gene, KSR1, play a critical role in determining how some tumor cells metabolize glucose. If we better understand the metabolism of cancer cells we may be able to produce new therapeutics.”
The article’s 26 authors hail from UNMC, the University of Cincinnati, the National Institutes of Health, Pfizer Global Research and Development, Penn State University, the U.S. Army Research Institute Environmental Medicine, Seahorse Bioscience and Washington University.
“I’m proud of the diverse set of collaborators that helped us study the biochemistry and physiology of KSR2,” Dr. Lewis said. “We could not have completed the project without their expertise and dedicated effort.”
As the state’s only academic health science center, UNMC is on the leading edge of health care. Breakthroughs are possible because hard-working researchers, educators and clinicians are resolved to work together to fuel discovery. In 2009, UNMC’s extramural research support topped $100 million for the first time, resulting in the creation of 3,600 jobs in Nebraska. UNMC’s academic excellence is shown through its award-winning programs, and its educational programs are responsible for training more health professionals practicing in Nebraska than any other institution. Through its commitment to education, research, patient care and outreach, UNMC and its hospital partner, The Nebraska Medical Center, have established themselves as one of the country’s leading health care centers. UNMC’s physician practice group, UNMC Physicians, includes 550 physicians in 50 specialties and subspecialties who practice primarily in The Nebraska Medical Center. For more information, go to UNMC’s Web site at www.unmc.edu.