Obesity Leads To Reversible Changes In Diabetes-Predisposition Genes

MedicalResearch.com interview
Dorota Kaminska, MSc
Department of Clinical Nutrition
University of Eastern Finland

MedicalResearch: What is the background for this study? What are the main findings?

Response: The prevalence of obesity is increasing worldwide, making it one of the biggest health problems currently facing both developed and developing countries. Obesity is considered a primary risk factor for developing type 2 diabetes. While the majority of people with type 2 diabetes are obese, most of obese people do not develop diabetes, indicating that obesity is not the only risk factor for type 2 diabetes. Both obesity and type 2 diabetes are multifactorial complex diseases that are caused by a combination of genetic, environmental, and lifestyle factors. Results from twin studies suggest that genetic factors explain 50% to 90% of the variance in body mass index (BMI) and from 45% to 85% of the diabetes risk. However genetic variations identified by genome wide association studies (GWAS) explain only 2-4% of the obesity risk and 5-10% of the type 2 diabetes risk. Several options have been debated to be a source of so called “missing heritability”, including, among others, structural DNA variations, gene-gene and gene-environment interactions, epigenetic modifications and RNA splicing.

We used adipose tissue samples from Kuopio Obesity Surgery (KOBS), very low calorie diet (VLCD), Metabolic Syndrome in Men (METSIM) and European Network on Functional Genomics of Type 2 Diabetes (EUGENE2) studies to determine alternative splicing pattern of selected genes.

The study focused on determining the effects of obesity and weight loss on alternative splicing of metabolically active genes (TCF7L2 and INSR). We showed that alternative splicing of both genes is dysregulated in obesity and type 2 diabetes, resulting in impaired insulin action in adipose tissue. Additionally we demonstrated, that obesity induced changes in splicing can be reversed by weight loss induced by gastric bypass surgery or very low calorie diet.

Furthermore, the study identified alternatively spliced genes in the genomic regions associated with obesity risk, demonstrating that splicing of the MSH5 gene in subcutaneous fat is regulated by weight loss. The study also found that body mass index is a main determinant of TRA2B, BAG6 and MSH5 splicing in subcutaneous fat; however, the functional consequences of this finding require further investigation. These findings imply that the obesity-associated gene variants might act through regulation of splicing which in turn might underlie the pathogenesis of obesity in individuals carrying the risk variants.

MedicalResearch: What should clinicians and patients take away from your report?

Response: Our study indicates that although obesity leads to the changes in splicing of metabolically active genes resulting in increased risk of developing type 2 diabetes, the lifestyle change resulting in weight loss can reverse the process leading to improvement of insulin action. Our findings additionally support the positive impact of lifestyle changes on type 2 diabetes prevention. There is certainly much more to discover about alternative splicing function in pathophysiology of metabolic disorders. Furthermore, it is possible that treatments, which target a particular splicing of metabolically active genes might reduce type 2 diabetesdiabe risk. Future studies, should improve the chances for a more targeted treatment and more accurate diagnostics and possible personalized therapeutic approaches.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Response: Our findings emphasize an important role of alternative splicing in mediating the gene-environment interaction. Future studies should include a genome wide analyses of alternative splicing in metabolically relevant tissues and their relation to known risk gene variants as well as the genome wide association between alternative splicing and obesity and weight loss. These studies should provide a better understanding of the relationship between alternative splicing, genotypes and obesity and/or type 2 diabetes on genome wide scale.

Citation:

Regulation of Alternative Splicing in Obesity and Weight Loss
Doctoral Dissertation
May 21, 2015 University of Eastern Finland

MedicalResearch.com interview, & Dorota Kaminska, MSc (2015). Obesity Leads To Reversible Changes In Diabetes-Predisposition Genes