Impact of Gq signaling in the brown adipose tissue

哺乳动物的脂肪有两种主要类型：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专门消耗能量，这种能量是由棕色脂肪细胞特有的线粒体蛋白UCP-1(解偶联蛋白-1)介导的。这一过程也被称为非颤抖产热，对于新生儿在寒冷的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，成年人也拥有代谢活跃的蝙蝠，蝙蝠的质量与人类的苗条有关。因此，BAT是新的抗肥胖疗法的潜在靶点，由于肥胖症已经达到流行病的规模，近20亿人超重或肥胖，因此迫切需要这种疗法。除了经典的蝙蝠外，在Wat中还发现了棕色样脂肪细胞(即所谓的米色或棕色(白色中的棕色)细胞)。棕色和米色细胞被G蛋白偶联受体(GPCRs)激活，G蛋白偶联受体与GalpHas相连，增加环磷酸腺苷(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Galpas和Galphai连接的受体外，人们对其他GPCRs及其在BAT中的作用知之甚少。我们基于棕色脂肪细胞中存在的GPCRs的无偏筛查的初步数据表明，相当多的GPCRs与Galphaq相关联。研究单位给了我们独特的机会来确定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(这项研究的重点是从植物中提取的分子)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.