Are there changes that affect genes and fuel a person’s propensity to develop obesity? That’s a question under study at Texas Biomedical Research Institute. Associate Scientist Melanie Carless, Ph.D., is Principal Investigator of a $3 million, four-year grant from the National Institute of Diabetes, Digestive and Kidney Diseases to research this hypothesis.
The Centers for Disease Control calls U.S. obesity an “epidemic,” with 40% of adults and 19% of children considered obese. Within children, however, there are disparities among ethnicities. Hispanic children have the highest rate of obesity at 26% compared to African American (22%), Caucasian (14%), and Asian (11%) children.
Dr. Carless and her collaborators will be studying an area of research called epigenetics – which describes changes to our DNA, RNA, or proteins that are affected by both the environment and genetic makeup and that regulate gene and protein expression. Her team will be examining a specific area of epigenetics, DNA methylation, which is capable of switching genes on and off.
“If we start at the cellular level and then look at whole organisms like the human body and how we use energy, then we can identify pathways that are involved in the development of obesity and also potentially mechanisms by which we can intervene and treat obesity,” Dr. Carless explained, “we are trying to relate changes at a person’s cellular level to the physical expression of obesity to identify mechanisms for treatment.”
The first part of the study involves a group of 900 Texas Hispanic children who have a high propensity for obesity. Scientists will combine physical data like caloric intake, physical activity, energy expenditure, metabolic rate and glucose levels with another factor measured in a blood sample called DNA methylation. Methylation is a biochemical process where methyl groups are added to DNA in a way that changes the expression of certain genes, and often the production of proteins. They will test whether methylation of specific genes is related to the physical data collected to increase risk for obesity.
In the second phase of the study, scientists will compare changes in blood with changes in muscle tissue and muscle cells and see how these changes correlate. Using blood samples, scientists will induce pluripotent stem cells (or master cells) which can be directed to develop into skeletal muscle cells for experimentation.
Part three of the study involves the use of CRISPR (a new technology to alter DNA sequences and modify gene function) to go into cells and change the methylation levels at specific sites to see what impact that has on the cells and how they might utilize energy. That information could lead to more targeted drug therapies for obesity, or someday, editing to correct an underlying issue at the DNA level.
“I think it’s really important,” Carless explained. “Obesity can be a huge factor in serious medical problems including diabetes, high blood pressure, atherosclerosis, and heart disease. We need to understand how obesity develops at a young age and the impact this might have on health later in life. If we can start to reduce the rates of obesity in the U.S., we will start to see a decline in multiple other disorders.”
Collaborators on the study include co-investigator Shelley Cole, Ph.D., an Associate Scientist at Texas Biomed. Cole manages the cohort DNA samples and data. Texas Biomed Associate Scientist Tiziano Barberi, Ph.D., is also a co-investigator. Dr. Barberi has developed a protocol to generate skeletal muscle cells from induced pluripotent stem cells (iPSCs). Co-investigator Mark Kos, Ph.D. of the University of Texas Rio Grande Valley is a statistical geneticist and bioinformatician who will analyze the data. Yidong Bai, Ph.D., of the University of Texas Health Science Center at San Antonio is another co-investigator who is an expert in the field of mitochondrial function. He will design validation experiments for assays that examine cellular metabolism. Two consultants on the project are Nancy Butte, Ph.D., Baylor College of Medicine, and Dawn Coletta, Ph.D., University of Arizona Health Sciences.
This research – Epigenetics of Energy Homeostasis, Bioenergetics and Obesity — is supported by Grant #R01DK118630 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health.