Impact of Gq signaling in the brown adipose tissue

哺乳动物的脂肪主要有两种：白色脂肪组织（WAT）和棕色脂肪组织（BAT）。与储存能量最多的WAT不同，BAT专门耗散能量，这是由棕色脂肪细胞特异性线粒体蛋白UCP-1（解偶联蛋白-1）介导的。这个过程也被称为非寒颤产热，对新生儿在寒冷环境中保持体温至关重要。重要的是，最近使用葡萄糖示踪剂的研究清楚地表明，成年人也具有代谢活跃的BAT，并且BAT的质量与人类的瘦度相关。因此，BAT是新型抗肥胖疗法的潜在靶点，由于肥胖已达到流行病的程度，近20亿人超重或肥胖，迫切需要这种疗法。除了经典的BAT外，在WAT中还发现了棕色样脂肪细胞（即所谓的米色或白褐色细胞）。棕色和米色细胞被G蛋白偶联受体（gpcr）激活，该受体与Galphas连接并增加环AMP （cAMP）。cAMP激活蛋白激酶A，进而诱导脂肪分解并激活棕色和米色脂肪细胞中的UCP-1。相反，galphai偶联受体抑制cAMP的产生和棕色脂肪细胞的激活。除了Galphas-和Galphas- linked受体外，对其他gpcr及其在BAT中的作用知之甚少。我们基于褐色脂肪细胞中gpcr的无偏筛选的初步数据显示，这些gpcr中有相当一部分与Galphaq相关。该研究单位为我们提供了独特的机会来确定Galphaq信号在棕色和米色脂肪中的作用。我们将使用选择性Galphaq抑制剂FR 900359（一种植物来源的分子，是本研究计划的重点）和RU中产生的新化合物以及包括慢病毒载体和转基因动物在内的遗传工具，研究Galphaq在人类棕色和米色脂肪细胞以及小鼠BAT和WAT中的功能。

Two major types of fat can be distinguished in mammals: white adipose tissue (WAT) and brown adipose tissue (BAT). In contrast to WAT, which is the largest store of energy, BAT is specialized in dissipating energy, which is mediated by the brown adipocyte-specific mitochondrial protein UCP-1 (uncoupling protein-1). This process is also known as non-shivering thermogenesis and is essential for newborns to maintain body temperature in a cold environment. Importantly, recent studies using glucose tracers clearly showed that adults also possess metabolically active BAT and that BAT mass correlates with leanness in humans. Thus, BAT is a potential target for novel anti-obesity therapies, which are urgently needed since obesity has reached pandemic dimensions with nearly two billion people being overweight or obese. In addition to classical BAT, brown-like adipocytes (so called beige or brite (brown in white) cells) have been found in WAT. Brown and beige cells are activated by G protein coupled receptors (GPCRs) that are linked to Galphas and increase cyclic AMP (cAMP). cAMP activates protein kinase A, which in turn induces lipolysis and activates UCP-1 in brown and beige adipocytes. In contrast, Galphai-coupled receptors inhibit cAMP production and brown adipocyte activation. Apart from Galphas- and Galphai-linked receptors not much is known about other GPCRs and their role in BAT. Our preliminary data based on an unbiased screen of GPCRs present in brown adipocytes show that a considerable number of these GPCRs are linked with Galphaq. The Research Unit gives us the unique opportunity to identify the role of Galphaq signalling in brown and beige fat. We will study Galphaq function in human brown and beige fat cells as well as in murine BAT and WAT using the selective Galphaq inhibitor FR 900359 (a plant-derived molecule that is in the focus of this research initiative) and novel compounds generated in the RU as well as genetic tools including lentiviral vectors and transgenic animals.