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

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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.