Regulators of metabolic co-morbidities

Regulators of metabolic co-morbidities

Lay summary

Obesity has become highly prevalent in the human population, and obesity enhances the risk for developing a wide range of diseases, including diabetes, brain dysfunction, inflammation, and cancer. However, it is unclear what determines which obese individual will go on to develop one of these diseases and which one will not. Our study aims at identifying genetic and lifestyle factors that regulate an individual's path to health or disease. This study, which we estimate to run for three years, will enable us to develop simple tests to predict an individual's risk for developing obesity-associated diseases. It will also greatly enhance our basic understanding of the factors that work together with obesity in enhancing the disease risk in various tissues of the human body.

Scope extension, April 2024:

Obesity is often associated with metabolic syndrome, cancer, inflammatory disorders, neurodegeneration, and other diseases. However, not all obese patients develop these co-morbidities. The aim of this study is to unravel genetic and environmental variants associated with diseases that accompany obesity.

The premise of this proposal is to understand the effects of common and less common genetic variants, psychosocial, and environmental factors on metabolic traits and diseases.

The liver is a central organ of human metabolism and highly affected by obesity. The liver is closely connected with the gut, receives 2/3 of its blood supply via the portal vein, and constantly exposed to a vast amount of molecules and other metabolites from the intestine. We aim to investigate the interaction between genetics, psychosocial, and environmental factors (e.g. smoking, alcohol use, medication, dietary intake, physical activity). Understanding the complex relationship between gut and liver and their interaction with obesity has the potential to greatly improve patient stratification and identification of populations at risk of these outcomes. The proposed research could significantly improve knowledge of the biological mechanisms that lead to metabolic disease, refine disease prevention, and detect new types of markers for early detection and/or intervention. This information can help healthcare professionals advance treatment and prevention strategies for various cardiometabolic outcomes.

Among the conditions associated with obesity is inflammatory bowel disease (IBD). Accompanied by the rise of obesity, we observe a strong increase in diseases associated with a high level of psychological stress such as depression and anxiety. We therefore aim to assess obesity and psychosocial stress as an important non-genetic variable contributing to the individual susceptibility to develop inflammatory disorders such as IBD. Interestingly, preclinical data suggest that stress by itself exacerbates chronic inflammation. We hypothesize that UKB participants with IBD suffering from comorbid psychological stress will display an increased risk of developing IBD as well as a more severe course of the disease.