MedicalResearch: What are the main findings of the study?
Dr. Mani: Our group has identified a gene that when mutated it causes a form of truncal (central) obesity that is associated with a cluster of coronary artery disease risk factors, including high blood pressure, insulin resistance and possibly elevated blood lipids. These associated risk factors are collectively known as the metabolic syndrome, which may lead to development of diseases such as diabetes and coronary artery disease, both of which were very prevalent in the populations we studied. All identified mutations by our group have been so far gain of function mutations, which means they increased the activity of the gene in pathways related to adipogenesis and gluconeogenesis.
MedicalResearch: Were any of the findings unexpected?
Dr. Mani: Typically, metabolic syndrome and all of its components are believed to be caused by multiple genetic mutations and gene-environment interactions. Rarely, the syndrome may be caused by mutations in one single master gene that plays a key role in diverse metabolic pathways. It is unpredictable which family or population may harbor such mutations until we screen hundreds of them. It was, therefore, unanticipated to find 3 kindreds from one small town with strong family history of childhood obesity and coronary artery disease to share a common so called “founder” mutation.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Mani: The functional analysis of this disease gene and similar genes in other species such as mice, fruit fly and in yeast has so far shown that it is involved in pathways that regulate blood glucose levels, body weight and formation of adipose tissue and in these processes it interacts with the environment. In particular its function seems to be influenced by nutrients.
Several conclusions can be drawn from our study. First of all, our results confirm earlier findings that obesity can be an inherited disease. In addition, functional analysis of this gene has suggested that the environment and specifically the type of food one eats maybe equally important for the genetic mutation to wield its effect and cause disease.
A particular importance of our discovery is that the identified gene is an enzyme (a kinase) that can be targeted by drugs. Our future studies may determine if inhibiting the kinase-dependent or independent activities of the gene will be beneficial in preventing diabetes and heart disease. Our actual goal is to explore disease pathways in patients with these mutations and in animal models of this disease in order to identify novel risk factors for the disease of the general population and identify the optimal target for drug development.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Mani: There is growing evidence that the process of childhood obesity and its associated disorders may be initiated by alterations in function of cells known as mesenchymal stem cell. These cells give rise to different tissues, including skeletal muscle, bone and adipose tissue. Based on our preliminary results we believe that the identified mutation changes the fate of these cells leading to their preferential transformation into fat cells at the expense of formation of new skeletal muscle or bone tissue. These changes may ultimately lead to impaired insulin sensitivity. Future studies may have to focus on mechanisms of transformation in mesenchymal stem cells and how they can be manipulated in order to improve generation of insulin sensitive tissues.
Ali R. Keramati, M.D., Mohsen Fathzadeh, Ph.D., Gwang-Woong Go, Ph.D., Rajvir Singh, Ph.D., Murim Choi, Ph.D., Saeed Faramarzi, M.D., Shrikant Mane, Ph.D., Mohammad Kasaei, M.D., Kazem Sarajzadeh-Fard, M.D., John Hwa, M.D., Ph.D., Kenneth K. Kidd, Ph.D., Mohammad A. Babaee Bigi, M.D., Reza Malekzadeh, M.D., Adallat Hosseinian, M.D., Masoud Babaei, M.D., Richard P. Lifton, M.D., Ph.D., and Arya Mani, M.D.