Central and peripheral actions of FGF21 in promoting fat catabolism (invited resubmission)

这项研究的目的是了解新激素成纤维细胞生长因子21（FGF 21）如何以及在体内何处起作用，以减少食物摄入，减轻体重和调节体脂。这种激素是在十多年前首次发现的，但我们不确定身体中的哪些组织产生它，它在哪里起作用，以及它在我们生物学中的正常作用是什么。我们以前的研究利用了西伯利亚仓鼠体重的季节性周期，因为这提供了夏季体重增加（脂肪状态）和冬季体重减轻（瘦状态）的自然动物模型。使用这个模型，我们已经发现FGF 21在减少季节性肥胖仓鼠的食欲和减肥方面更有效。这是一个非常重要的发现，因为对其他主要代谢激素的反应在高体脂状态下通常会降低。肥胖是一种胰岛素和瘦素抵抗状态，这一事实为使用这些途径来管理体重紊乱提出了挑战。因此，了解FGF 21的天然生物学对于肥胖的药物和/或营养治疗具有重要意义，因为该途径可能易于操纵。第一个目标是确定哪些组织通过改变其对葡萄糖和脂肪酸的摄取来响应FGF 21治疗。这将使用小动物正电子发射断层扫描（PET）扫描仪来实现，该扫描仪允许在活体动物中非侵入性地观察这些代谢物的摄取。我们还将在体外测试FGF 21是否可以促进脂肪分解。这些研究将确定哪些组织是FGF 21作用的主要靶点，并确认对葡萄糖和脂肪酸摄取的作用是否是对脂肪库和体重的全身影响的基础。第二个目标是调查FGF 21也在大脑中起作用以减少食物摄入和增加能量消耗的假设。其他代谢激素，如瘦素和胃饥饿素，分别从脂肪和胃向大脑发出信号，以调节我们的食欲。我们的初步研究也提供了证据表明FGF 21可以在大脑中发挥作用。我们特别感兴趣的是对下丘脑中一层称为伸长细胞的神经胶质细胞的作用，因为这些细胞表达称为FGFR 1c的FGF 21受体，并显示出对这些受体刺激的基因表达和葡萄糖刺激的钙信号的变化。我们将通过确定直接将FGF 21本身或由制药公司Eli Lilly开发的密切相关的化合物施用到大脑中是否会改变食欲，能量消耗和体重来验证这一假设。我们还将使用来自啮齿类动物的脑切片成像来确定FGF 21是否直接影响神经元和神经胶质细胞。该项目的总体结果是，我们将了解激素FGF 21如何能够产生改善葡萄糖分散和身体脂肪损失的有益效果。我们将确定哪些组织对FGF 21有反应，并将确定其部分作用是否通过控制行为和自主神经系统在大脑中发挥作用。这个项目的受益者很多。所获得的信息将对大学和研究机构的其他学术研究人员以及从事肥胖研究的制药行业的研究人员非常重要。此外，该项目将提供先进的成像和实验生理学方面的培训，研究人员将促进公众对食欲控制和肥胖研究的理解。

The purpose of this research is to understand how and where in the body the novel hormone fibroblast growth factor 21 (FGF21) acts to reduce food intake, decrease body weight and regulate body fat. This hormone was first discovered over ten years ago, but we are uncertain about which tissues in the body produce it, where it acts, and what its normal role in our biology is. Our previous research has exploited seasonal cycles in body weight in the Siberian hamster, as this provides a natural animal model of body weight gain in summer (fat state) and loss in winter (lean state). Using this model, we have already found that FGF21 is more effective at reducing appetite and causing weight loss in seasonally fat hamsters. This is a hugely important finding, because responses to other major metabolic hormones are often decreased in states of high body fat. The fact that obesity is an insulin- and leptin-resistant state presents challenges for using these pathways to manage body weight disorders. Understanding the natural biology of FGF21 should therefore have important implications for pharmaceutical and/or nutritional treatment of obesity as this pathway is likely to be amenable to manipulation. The first objective is to determine which tissues respond to FGF21 treatment by changing their uptake of glucose and fatty acids. This will be achieved using a small animal positron emission tomography (PET) scanner, which allows uptake of these metabolites to be observed non-invasively in living animals. We will also test in vitro whether FGF21 can promote fat breakdown. These studies will identify which tissues are the primary targets of FGF21 action, and confirm whether actions on glucose and fatty acid uptake underlie the whole body effects on fat depots and body weight.The second objective is to investigate the hypothesis that FGF21 also acts in the brain to reduce food intake and to increase energy expenditure. Other metabolic hormones such as leptin and ghrelin are known to signal from fat and the stomach respectively to the brain to regulate our appetite. Our preliminary studies also provide evidence that FGF21 can act in the brain. We are particularly interested in actions on a layer of glial cells in the hypothalamus known as tanycytes, as these cells express a receptor for FGF21 known as FGFR1c, and show changes in gene expression and glucose-stimulated calcium signalling in response to stimulation of these receptors. We will test the hypothesis by determining whether administration directly into the brain of FGF21 itself or a closely related compound developed by the pharmaceutical company Eli Lilly changes appetite, energy expenditure and body weight. We will also use imaging of slices of brain derived from rodents to determine whether FGF21 directly affects neurons and glial cells.The overall outcome of this project is that we will understand how the hormone FGF21 is able to produce its beneficial effects of improved glucose dispersal and loss of body fat. We will have identified which tissues respond to FGF21, and will determine if part of its action is in the brain via the control of behaviour and the autonomic nervous system. There are many beneficiaries of this project. The information gained will be important for other academic researchers in universities and in research institutes, and for researchers in the pharmaceutical industry working on obesity. In addition, the project will provide training in advanced imaging and experimental physiology, and the researchers will promote public understanding of research into appetite control and obesity.