Mechanisms for regulation of a novel class of anti-diabetic lipids

肥胖和2型糖尿病的日益流行需要新的预防和治疗策略。 我们发现了一种结构新颖的内源性生物活性脂质家族，即支链脂肪酸酯， 羟基脂肪酸（FAHFA）。一个亚科，羟基硬脂酸的棕榈酸酯（PAHSAs），具有 抗糖尿病和抗炎作用。胰岛素抵抗患者的血清和脂肪组织中PAHSA水平较低， 与胰岛素敏感的人相比，水平与胰岛素敏感性高度相关。胰岛素抵抗 在小鼠中，PAHSA给药改善葡萄糖耐量和胰岛素敏感性，部分是通过增强胰岛素 抑制肝脏葡萄糖产生的作用，这是由改善的脂解抑制引起的。PAHSA是 抗炎和降低结肠炎的严重程度和小鼠自身免疫1型糖尿病的发病率。我们 在发现PAHSAs的新活动方面取得了巨大的进步，确定了更多的PAHSAs家族， 生物活性和储存形式的FAHFA，并揭示生化途径和酶，控制 组织FAHFA水平。这些研究强调，FAHFA是一类高度调节的脂质， 巨大的转化潜力本提案的总体目标是确定 在生理和疾病状态下通过鉴定酶调节组织和血清FAHFA水平， 调节FAHFA生物合成、降解和掺入其他脂质的途径。我们将使用 创新和强大的检测，我们开发了同位素标记的FAHFA及其前体，以测量 体内FAHFA合成和降解，靶向FAHFA调控的特定途径，并鉴定 另外，缺失的酶和其他调节FAHFA生物合成、降解、运输和代谢的因子， 存储.我们已经通过鉴定3种FAHFA水解酶和第一种FAHFA， 生物合成转酰酶我们将描绘这种新的生物合成途径，使用新的机制研究。 我们还提出了一个高度互补的，创新的，系统分析，将整合转录组数据 有针对性的FAHFA测量。首先，我们将利用大规模的互惠监管， 在我们独特的Glut 4和ChREBP表达改变的小鼠模型中， 调解这一规定。由于人体脂肪组织中Glut 4和ChREBP的表达与 胰岛素敏感性和脂肪FAHFA水平，这些实验鉴定的基因可能具有临床意义。 本案无关第二种方法利用了多样性远交（DO）小鼠的自然遗传变异， 和人类一样有着天然的遗传变异。我们将有针对性地 在~500只DO小鼠的脂肪组织、肝脏和血浆中测量~300种不同的FAHFA异构体， 利用来自DO小鼠的现有遗传和转录组学数据来寻找新的组织“驱动因子”/调节因子， FAHFA水平。这些研究将促进我们对FAHFA生物学在健康和疾病方面的理解， 有可能发现新的酶和途径的脂质代谢，可以针对临床效益。

The growing epidemic of obesity and Type 2 diabetes requires new strategies for prevention and treatment. We discovered a structurally novel, family of endogenous bioactive lipids, branched fatty Acid esters of Hydroxy fatty Acids (FAHFAs). A subfamily, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), has anti-diabetic and anti-inflammatory effects. PAHSA levels are low in serum and adipose tissue of insulin-resistant versus insulin-sensitive people, and levels correlate highly with insulin sensitivity. In insulin-resistant mice, PAHSA administration improves glucose tolerance and insulin sensitivity, in part by enhancing insulin action to suppress hepatic glucose production which results from improved lipolysis suppression. PAHSAs are anti-inflammatory and reduce colitis severity and the incidence of auto-immune Type 1 diabetes in mice. We have made tremendous strides in discovering new activities for PAHSAs, identifying additional families of bioactive and storage forms of FAHFAs, and uncovering biochemical pathways and enzymes that control tissue FAHFA levels. These studies underscore that FAHFAs are a highly-regulated class of lipids with tremendous translational potential. The overall objective of this proposal is to determine the mechanisms that regulate tissue and serum FAHFA levels in physiologic and disease states by identifying enzymes and pathways that regulate FAHFA biosynthesis, degradation and incorporation into other lipids. We will use innovative and robust assays we developed with isotopically-labeled FAHFAs and their precursors to measure FAHFA synthesis and degradation in vivo, target specific pathways of FAHFA regulation, and identify additional, missing enzymes and other factors that regulate FAHFA biosynthesis, degradation, transport and storage. We have already made terrific progress by identifying 3 FAHFA hydrolases and the first FAHFA biosynthetic transacylase. We will delineate this new biosynthetic pathway using novel mechanistic studies. We also propose a highly complementary, innovative, systems analyses that will integrate transcriptomic data with targeted FAHFA measurements. First, we will take advantage of the large, reciprocal regulation of FAHFAs in our unique mouse models with altered expression of Glut4 and ChREBP, to find unknown factors mediating this regulation. Since Glut4 and ChREBP expression in adipose tissue from humans correlates with insulin sensitivity and adipose FAHFA levels, genes identified with these experiments could have clinical relevance. The second approach exploits the natural genetic variation in the diversity outbred (DO) mice, which have as much natural genetic variation as the human population. We will perform targeted measurements of ~300 different FAHFA isomers in adipose tissue, liver and plasma of ~500 DO mice and leverage the existing genetic and transcriptomic data from DO mice to find new "drivers"/regulators of tissue FAHFA levels. These studies will advance our understanding of FAHFA biology in health and disease and potentially uncover novel enzymes and pathways in lipid metabolism that can be targeted for clinical benefit.