Metabolic diseases, such as obesity and type 2 diabetes, have risen to epidemic proportions in the U.S. and occur in about 30 percent of the population. Skeletal muscle plays a prominent role in controlling the body's glucose levels, which is important for the development of metabolic diseases like diabetes.
In a recent study, published in The Journal of Clinical Investigation, University Hospitals (UH) Cleveland Medical Center and Case Western Reserve University School of Medicine researchers have found that skeletal muscle significantly affects how the body stores and metabolizes fat.
In the study, Mukesh K. Jain, MD, senior author, Chief Academic Officer at UH, and the Ellery Sedgwick Jr. Chair & Distinguished Scientist, and his team set out to investigate the role of a gene called Kruppel-like factor 15 (KLF15) in skeletal muscle. The team utilized a mouse model with KLF15 specifically deleted in muscle.
This genetic manipulation resulted in a striking phenotype: obesity, dyslipidemia (high circulating levels of fats), glucose intolerance, insulin resistance, and a propensity to develop non-alcoholic fatty liver disease (NAFLD). Further investigation revealed that KLF15 controls skeletal muscle fat uptake and utilization. Without KLF15, fats cannot efficiently enter muscle and instead are deposited in the liver and white adipose tissue.
"We knew from prior work by our team that the role of KLF15 was critical for muscle health, because levels are increased in humans following exercise," explained Dr. Jain, who is also a Professor of Medicine and Vice Dean of University Hospitals Affairs at Case Western Reserve, and Chief Scientific Officer, Harrington Discovery Institute at UH. "Experimentally, muscle loss of KLF15 led to a reduction in exercise capacity in mice. The fact that KLF15 is also important in metabolic health is really exciting as it provides a potential molecular link between exercise and overall health."
The researchers further showed that a diet rich in short chain fatty acids (SCFAs) can improve aspects of metabolic disease. High-fiber foods, such as fruits, vegetables, beans and whole grains are rich in SCFAs. Mice given this diet showed decreased weight gain and improved glucose homeostasis (blood sugar regulation). Additionally, obese mice given this same diet demonstrated increased weight loss and improved insulin sensitivity, indicating that SCFA-rich diets can potentially serve as both a preventive and therapeutic avenue for metabolic disease.
"This predisposition to develop obesity and NAFLD both in the presence of caloric excess underscores the importance of skeletal muscle fat metabolism and organ cross-talk in the development of these serious diseases," said Liyan Fan, first author on the study. "This helps us understand the different players that contribute to metabolic disease, and consequently, identify targets for effective therapies."
Collectively, these findings identified skeletal muscle as an important regulator of fat metabolism and liver health, and SCFA-rich diets may be an effective and accessible supplemental therapy option for metabolic disease resulting from impaired fat handling.
Next steps in this research involve exploring muscle KLF15's role in different nutritional statuses (i.e. fasting and exercise), and investigating the therapeutic potential of targeting muscle KLF15.
Fan, L., et al. "Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis." The Journal of Clinical Investigation. DOI: 10.1172/JCI139496
This work was supported by the NIH, the American Heart Association AHA Established Investigator Award, the AHA-Allen Frontiers Award, and the Leducq Foundation Transatlantic Network of Excellence. Part of this study was performed at the National MMPC at University of Massachusetts Medical School, the University Cincinnati MMPC Center, Case Western Reserve MMPC, and Case Western Reserve Cryo-Electron Microscopy Core.
About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 19 hospitals (including 4 joint ventures), more than 50 health centers and outpatient facilities, and 200 physician offices in 16 counties throughout northern Ohio. The system's flagship academic medical center, University Hospitals Cleveland Medical Center, located in Cleveland's University Circle, is affiliated with Case Western Reserve University School of Medicine. The main campus also includes University Hospitals Rainbow Babies & Children's Hospital, ranked among the top children's hospitals in the nation; University Hospitals MacDonald Women's Hospital, Ohio's only hospital for women; University Hospitals Harrington Heart & Vascular Institute, a high-volume national referral center for complex cardiovascular procedures; and University Hospitals Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, including cancer, pediatrics, women's health, orthopedics, radiology, neuroscience, cardiology and cardiovascular surgery, digestive health, transplantation and urology. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including "America's Best Hospitals" from U.S. News & World Report. UH is also home to Harrington Discovery Institute-part of The Harrington Project for Discovery & Development. UH is one of the largest employers in Northeast Ohio with 28,000 physicians and employees. Advancing the Science of Health and the Art of Compassion is UH's vision for benefitting its patients into the future, and the organization's unwavering mission is To Heal. To Teach. To Discover. Follow UH on LinkedIn, Facebook @UniversityHospitals and Twitter @UHhospitals. For more information, visit UHhospitals.org.
About Case Western Reserve University
Case Western Reserve University is one of the country's leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,100 undergraduate and 6,700 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.
Journal of Clinical Investigation