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

脂肪源性 MIF 的调节：PAR2 介导的前脂肪细胞的新型分泌功能

• 批准号: RGPIN-2017-04542
• 负责人: Qi, Dake
• 金额: $ 3.79万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746270
• 关键词: regulation; adipose; derived; MIF; novel

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.

脂肪组织通常被认为是负责能量储存、温度调节和伤口愈合的器官系统，但它也是重要的内分泌器官，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，揭示这些机制将具有重要的意义，动物的生理和生物化学。因此，我们的长期目标是阐明脂肪组织如何作为内分泌器官协调全身代谢。我们未来5年的短期目标是研究参与脂肪源性蛋白质巨噬细胞迁移抑制因子（MIF）合成和释放调节的信号级联。MIF是一种进化上保守的蛋白质，由三个相同的单体组成，具有独特的互变异构酶活性，可催化D-多巴色素转化为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）中发现，并且它响应于刺激而从预先形成的储存池中释放。MIF还广泛表达于代谢活性组织，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。从脂肪组织释放的MIF减弱外周组织（脂肪、骨骼肌和肝脏）中的胰岛素信号传导，因此其在能量代谢中起关键作用。然而，目前尚不清楚MIF的表达和释放是如何在脂肪组织中调节的。因此，我们目前的项目将采用一个全面的策略，涉及在体外和在体内的研究，利用各种技术在分子和细胞生物学，包括qPCR，western blot和免疫组织化学等。在本研究中，我们的目的是：（1）检查MIF的表达和释放从脂肪组织中响应脂肪分化。(2)明确PAR 2在介导脂肪组织中前脂肪细胞和MIF表达中的作用。(3)评估前脂肪细胞池和MIF表达对脂肪酸刺激的反应。我们相信，明确脂肪组织中MIF表达和释放的调控机制，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的影响。HQP包括研究生和荣誉课程的本科生将参与这个项目。学生将广泛接触到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。