The regulation of adipose-derived MIF: A novel secretory function of preadipocytes mediated by PAR2

脂肪组织通常被认为是一个负责能量储存、温度调节和伤口愈合的器官系统，但它也是一个重要的内分泌器官，分泌激素和炎症因子，介导哺乳动物的代谢过程。调节脂肪组织分泌功能的分子机制在很大程度上是未知的，揭示这些机制将对动物生理学和生物化学具有重要意义。因此，我们的长期目标是阐明脂肪组织作为内分泌器官如何协调全身代谢。我们未来5年的短期目标是研究参与脂肪衍生蛋白巨噬细胞迁移抑制因子（MIF）合成和释放调节的信号级联。MIF是一种进化保守的蛋白，由三个相同的单体组成，在非哺乳动物中具有独特的变异体酶酶活性，可催化d -多巴胺转化为5,6-二羟基吲哚-2-羧酸。在哺乳动物中，MIF首先在免疫细胞（巨噬细胞/单核细胞）中被发现，并在刺激下从预先形成的储存池中释放出来。MIF也广泛表达于代谢活跃的组织，包括脂肪组织、心脏和肝脏；其中，脂肪组织是血浆MIF的主要来源。脂肪组织释放的MIF可减弱外周组织（脂肪、骨骼肌和肝脏）的胰岛素信号，因此它在能量代谢中起关键作用。然而，目前尚不清楚脂肪组织中MIF的表达和释放是如何被调节的。因此，我们目前的项目将采用包括体外和体内研究在内的综合策略，利用各种分子和细胞生物学技术，包括qPCR， western blot和免疫组织化学等。在本研究中，我们的目标是：(1)检测脂肪组织中MIF的表达和释放对脂肪分化的反应。(2)明确PAR2在脂肪组织中介导前脂肪细胞和MIF表达中的作用。(3)评估脂肪酸刺激对前脂肪细胞池和MIF表达的影响。我们认为，确定脂肪组织中MIF的表达和释放机制将是揭示脂肪组织内分泌功能和发现脂肪组织如何协调全身代谢的重要努力。我们的发现可能会对动物生物学和生理学的学术研究产生长期影响。HQP包括研究生和荣誉项目本科生将参与该项目。学生将广泛接触自然科学的各种概念和实验技术。此外，研究生将根据目前提出的机制发展自己的研究兴趣。

Adipose tissue is commonly considered as an organ system responsible for energy storage, temperature regulation and wound healing, yet it is also an important endocrine organ which secrets hormones and inflammatory factors that mediate metabolic process in mammals. The molecular mechanisms in regulating the secretory function of adipose tissue are largely unknown and revealing these mechanisms will have important implications for animal physiology and biochemistry. Thus, our long-term goal is to elucidate how adipose tissue orchestrates whole-body metabolism as an endocrine organ. Our short-term goal for the next 5 years is to investigate the signaling cascades involved in the regulation of synthesis and release of an adipose derived protein, macrophage migration inhibitory factor (MIF). MIF is an evolutionarily conserved protein which is composed of three identical monomers and possesses unique tautomerase enzymatic activity to catalyze the conversion of D-dopachrome into 5,6-dihydroxyindole-2-carboxylic acid in non-mammalians. In mammals, MIF was first discovered in immune cells (macrophage/monocyte) and it was released from pre-formed storage pools in response to stimulation. MIF is also widely expressed in metabolically active tissues including adipose tissue, heart and liver; among these, the adipose tissue is the major resource of plasma MIF. MIF released from adipose tissue attenuates insulin signaling in peripheral tissues (adipose, skeletal muscle and liver) and thus it plays a key role in energy metabolism. However, it remains unclear how the expression and release of MIF is regulated in adipose tissue. Thus, our current project will employ a comprehensive strategy involving both in vitro and in vivo studies, utilizing various techniques in molecular and cellular biology including qPCR, western blot and immunohistochemistry etc.In this study, our aims are to:(1) Examine MIF expression and release from adipose tissue in response to adipose differentiation. (2) Define the role of PAR2 in mediating preadipocytes and MIF expression in adipose tissue. (3) Evaluate preadipocyte pool and MIF expression in response to fatty acid stimulation. We believe identifying the mechanisms in mediating the expression and release of MIF in adipose tissue will be an important effort to reveal the endocrine function of adipose tissue and discover how adipose tissue orchestrates whole-body metabolism. Our findings might have a long-term impact in academic studies of animal biology and physiology.HQP including graduate students and honors program undergraduate students will be involved in this project. The students will be widely exposed to various concepts and experimental techniques of natural sciences. In addition, graduate students will develop their own research interests based on the current proposed mechanisms.