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

本研究的目的是了解新型激素成纤维细胞生长因子21 （FGF21）如何以及在体内何处起作用，以减少食物摄入，降低体重和调节体脂。这种激素在十多年前首次被发现，但我们不确定身体的哪些组织会产生它，它在哪里起作用，以及它在我们的生物学中的正常作用是什么。我们之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）和冬季体重减少（瘦状态）的自然动物模型。使用这个模型，我们已经发现FGF21在减少季节性肥胖仓鼠的食欲和体重减轻方面更有效。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脂肪状态下通常会降低。肥胖是一种胰岛素和瘦素抵抗状态，这一事实为利用这些途径来控制体重失调提出了挑战。因此，了解FGF21的自然生物学应该对肥胖的药物和/或营养治疗具有重要意义，因为这一途径可能易于操纵。第一个目标是通过改变组织对葡萄糖和脂肪酸的摄取来确定哪些组织对FGF21治疗有反应。这将使用小型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无创地观察这些代谢物的摄取。我们还将在体外测试FGF21是否能促进脂肪分解。这些研究将确定哪些组织是FGF21作用的主要目标，并确认对葡萄糖和脂肪酸摄取的作用是否构成了对脂肪储存和体重的全身影响。第二个目标是调查FGF21在大脑中也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，如瘦素和胃促生长素，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FGF21可以在大脑中起作用的证据。我们对下丘脑中一层胶质细胞的作用特别感兴趣，因为这些细胞表达一种称为FGFR1c的FGF21受体，并在这些受体的刺激下显示出基因表达和葡萄糖刺激钙信号的变化。我们将检验这一假设，确定将FGF21本身或由礼来制药公司开发的一种密切相关的化合物直接注入大脑，是否会改变食欲、能量消耗和体重。我们还将使用来自啮齿动物的脑切片成像来确定FGF21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FGF21如何能够产生改善葡萄糖分散和减少体脂的有益作用。我们将确定哪些组织对FGF21有反应，并将确定其部分作用是否通过行为控制和自主神经系统在大脑中发挥作用。这个项目有很多受益者。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，该项目将提供高级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.