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

The overall aim of this project is to determine the sites and mechanisms of action by which FGF21 regulates body fat depots. This will be achieved by exploiting a natural animal model of body weight gain in long summer photoperiods, and weight loss in short winter photoperiods, where the body weight changes predominantly reflect changes in visceral adiposity: the Siberian hamster. Our pilot studies reveal that FGF21 and a monoclonal antibody (H7) which targets its likely receptor (FGFR1c) are more effective at reducing appetite and causing weight loss in seasonally fat hamsters as compared to those in the winter lean state, hence the importance of identifying where and how FGF21 exerts its effects. The first objective is to identify which tissues respond to FGF21. We will use 18F-2-deoxy-D-glucose and 16-18F-4-thia-palmitate tracers in a small animal quantitative positron emission tomography (PET)/nanoCT scanner to identify potential sites of action. Fat (long day) and lean (short day) hamsters will be tested, in the presence and absence of an insulin challenge. These in vivo studies will be complemented by ex vivo biochemical and molecular analysis of signal transduction pathways in tissues removed from the scanned animals, and by in vitro analyses of the effects of FGF21 on lipolysis and insulin secretion using isolated adipose tissue and beta cell islets, respectively. The second objective is to investigate the hypothesis that FGF21 also acts centrally to reduce food intake and to increase energy expenditure. We will determine whether administration of FGF21 directly into the brain (or a mimetic, LY2405319) changes appetite, metabolic rate, fat oxidation and body weight. We will also determine whether these central treatments alter gene expression and signalling in hypothalamic tanycytes, glial cell known to express FGFr1c which we have previously shown to mediate seasonal regulation of body weight via their regulation of the local thyroid hormone availability.