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

啮齿动物棕色脂肪组织(BAT)的能量消耗与食物诱导的产热作用有关。现在已经证实，健康的成年人类也拥有活跃的蝙蝠，分布在不同解剖位置的小仓库中。重要的是，人类的蝙蝠活动与BMI呈负相关。此外，在啮齿动物和人类中，在Wat储存库中出现棕色样脂肪细胞岛，称为Brite(白褐色)或米色脂肪细胞。识别增加BAT和Brite脂肪细胞质量/活性的因素将对超重/肥胖及其相关疾病(如2型糖尿病)的治疗具有重要意义。在缺乏有效和安全的肥胖药物治疗的情况下，开发营养干预措施来调节脂肪组织的代谢功能是一种很有前途的替代方法。膳食脂肪的脂肪酸组成的差异有助于脂肪组织的发育，特别是在n6至n3多不饱和脂肪酸(PUFAs)的相对摄入量方面。膳食中多不饱和脂肪酸的质量和数量决定了有机体中合成的脂肪酸代谢物的性质和多样性。这些代谢物在哺乳动物中被称为氧脂或二十烷基类化合物，参与各种生理和炎症过程，特别是在脂肪组织的发育和功能方面。在这里，我们将使用有针对性的营养干预来调节氧脂代谢。我们的目标是在小鼠和人类的脂肪组织中识别不同的氧脂，它们与Brite脂肪生成有关，因此能够增加能量消耗。代谢物分析将得到脂肪组织的转录组分析和肠道微生物区系测序的支持，以破译脂肪组织内营养干预调节的途径，以及肠道微生物组的相关变化。有意义的氧磷脂将在体外验证其诱导人类和小鼠细胞成脂和/或活性的能力。此外，利用药物抑制和siRNA或shRNA介导的关键酶的敲除，将在体外分析具有证实生物活性的氧脂合成途径。选定的氧脂的体内验证将使用Wat的原位植入性微丸进行，从而允许分子的持续释放。最后，具有最强生物活性的氧磷脂将在饮食干预研究中得到验证。我们的研究计划将阐明膳食脂肪成分在预防超重和肥胖方面的潜在作用。我们的研究项目涉及基础和医学研究，旨在更好地了解氧脂在Brite脂肪细胞形成中的作用机制，为开发新的治疗方法和商业应用铺平道路。

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.