DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

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

Submission summary

The increasing prevalence of overweight and obesity has reached “epidemic” proportions as documented by overweight (BMI > 25 kg/m2) in more than 1.9 billion people among which at least 600 million are clinically obese (BMI > 30 kg/m2). This causes major costs for our health care systems. Increase in body weight is accompanied by an increase in the mass of white adipose tissue (WAT) resulting from an imbalance in energy intake and energy expenditure. Pharmacological remedies or lifestyle interventions normalizing this imbalance with significant long-term success are not available. During the last two decades, the major scientific and financial contributions have focused on the identification of genetic modifiers of the response to”obesogenic'' environments. The results obtained so far appear rather disappointing with respect to public health issues. Regarding energy expenditure, brown adipose tissue (BAT) in rodents for a long time 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, BAT activity is inversely correlated with BMI. Furthermore, in rodents and humans, islands of brown-like adipocytes emerge within WAT depots after cold or ß3-adrenergic receptor stimulation. These adipocytes, termed “brite” (brown-in-white) or “beige” adipocytes, differ by embryonic origin from genuine brown adipocytes but are functional, i.e., thermogenically active. Therefore, the identification of factors increasing mass/activity of human BAT 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 omega6 to omega3 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 inWAT 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.

Project coordination

Ez-Zoubir Amri (Institut de Biologie de Valrose)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IBV Institut de Biologie de Valrose
TUM Center for Nutritional Medicine, Freising, Germany

Help of the ANR 261,080 euros
Beginning and duration of the scientific project: November 2015 - 36 Months

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