Testing the potency of nutritional interventions to modulate eicosanoid metabolism in adipose tissues and brite adipogenesis

• Applicant: Professor Dr. Martin Klingenspor
• Subject Area: Nutritional Sciences
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 284137073

Energy expenditure in brown adipose tissue (BAT) of rodents has been implicated in the dissipation of caloric excess through diet-induced thermogenesis. It is now established that healthy adult humans also possess active BAT, localized in small depots at various anatomical sites. Importantly, human BAT activity is inversely correlated with BMI. Furthermore, in rodents and humans, islands of brown-like adipocytes emerge within WAT depots after, termed brite (brown-in-white) or beige adipocytes. The identification of factors increasing mass/activity of BAT and brite adipocytes would be of great interest for the treatment of overweight/obesity and associated diseases such as type 2 diabetes. In the absence of effective and safe pharmaceutical treatments of obesity, the development of nutritional interventions to modulate metabolic functions of adipose tissues are a promising alternative approach. Differences in fatty acid composition of dietary fat contribute to adipose tissue development, in particular with respect to the relative intake of n6 to n3 poly-unsaturated fatty acids (PUFAs). Quality and quantity of dietary PUFAs determine the nature and diversity of fatty acid metabolites synthesized in the organism. These metabolites, named oxylipins or eicosanoids in mammals, are involved in various physiological and inflammatory processes, particularly in adipose tissue development and function. Here, we will employ nutritional interventions targeted to modulate oxylipin metabolism. We aim to identify distinct oxylipins in murine and human adipose tissues, which are associated with brite adipogenesis and thus able to increase energy expenditure. Metabolite analyses will be backed up by transcriptome analyses of adipose tissues and gut microbiota sequencing in order to decipher the pathways modulated by nutritional interventions within adipose tissues, and related changes in the gut microbiome. Oxylipins of interest will be validated in vitro for their capacity to induce brite adipogenesis and/or activity of human and murine cells. Additionally, pathways of oxylipin synthesis with confirmed bioactivity will be analyzed in vitro using pharmacological inhibition and siRNA or shRNA mediated knockdown of key enzymes. In vivo validation of selected oxylipins will be performed using implantable pellets in situ in WAT allowing a constant release of the molecule. Finally, oxylipins with the most potent bioactivities will be validated in dietary intervention studies. Our research program will shed light on the potential role of dietary lipid composition in the prevention of excess body weight gain and obesity. Our research program is related to fundamental and medical research and aims to gain a better understanding of the mechanisms underlying the role of oxylipins in brite adipocyte formation, paving a way for the development of new therapies and commercial applications.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Dr. Ez-Zoubir Amri