Role of Xenobiotics in Metabolic Diseases: A Translational Approach

Humans are daily exposed to environmental pollutants that may affect health. We investigated the health impacts of persistent organic pollutants, which are chemicals omnipresent in our food chain. We found that obese individuals with elevated levels of POPs are at high risk for cardio metabolic diseases compared with obese individuals with low POP levels. Furthermore, the use of environmental pollutants led us to discover a novel biological function of the fibroblast growth factor 19 (FGF19), a hormone secreted by the intestine. We demonstrated that chronic FGF19 injection increases skeletal muscle mass in mice and human muscle cells treated with FGF19 become larger than placebo-treated human cells. We are now trying to develop a FGF19-based drug to treat muscle atrophy diseases. Finally we found that POPs could significantly affect the biological function of mouse intestine, thus suggesting that POPs may have a role in inflammatory bowel diseases. Til slutt, fant vi ut at POP kunne påvirke den biologiske funksjonen av tarmen betydelig, noe som tyder på at POP kan ha en rolle i inflammatoriske tarmsykdommer.

The project has contributed to the following: * Advances our understanding of xenobiotics/environmental chemicals and their potential impacts on human health. * Scientific breakthrough about FGF19 and its therapeutic potential again muscle atrophy-linked diseases/disorders. We are now in dialogue with international pharmaceutical companies. * The findings of the project have helped the PI to build his own research team, extend his leadership skills and build up strong international network with leading experts in the field. Taken together, the present project may have important societal impacts in the close future.

Every day, the human body must defend itself against a myriad of potentially noxious xenobiotics (i.e. substances foreign to an entire biological system), and the health consequences of this exposure on our bodies have just begun to be investigated. Insulin resistance is strongly linked to metabolic diseases such as type 2 diabetes, obesity, and cardiovascular diseases. Today, the documented global increase in insulin resistance-related metabolic diseases, together with the poor efficacy of current preventive and therapeutic treatments, means that there is an urgent need to better understand the fundamental causes of insulin resistance. The present proposal represents a new direction that has not previously received much attention, but which is, in fact, pervasive in modern life today: the impact of environmental pollutants on metabolic diseases. TRANSITION is a project designed to radically advance environmental medicine research and renovate our understanding of metabolic diseases. Although t he present proposal can be considered risk-taking because it challenges traditional beliefs about the primary factors involved in contributing to metabolic diseases, my previous and on-going work have provided proof-of-concept for the project's objectives . TRANSITION is expected to not only fill important knowledge gaps in the field, but may also contribute to the development of a novel diagnostic tool that will detect the potential of chemicals to cause metabolic disruptions in humans. To achieve t his, TRANSITION aims to use a translational approach to establish links between in vitro and animal data with the real risks associated with human exposure to pollutants. In a project that bridges basic and applied research, TRANSITION proposes to use a m ulti-disciplinary approach that combines environmental toxicology, molecular biology and physiology, and to use original experimental models as well as a unique human patient study group.