Neuroendocrine control of bone and energy metabolism: the role of FGF21

Fibroblast Growth Factor 21 (FGF21) is a hepatic polypeptide that promotes glucose uptake in adipocytes, protects animals from diet-induced obesity when overexpressed in transgenic mice, and lower blood glucose and triglyceride levels when therapeutically administered to diabetic rodents. Recent studies have shown that FGF21 crosses the blood brain barrier and have suggested that FGF21 can thereby affect ingestive behaviours and sympathetic and hormonal control of peripheral targets eg brown fat, white fat and bone. This project will exploit an animal model of natural obesity and weight loss comprising seasonal cycles of energy metabolism in the Siberian hamsters. The project builds upon studies by previous BBSRC-funded students showing that hepatic production of FGF21 increases in hamsters under short photoperiods so is associated with the winter catabolic state. The specific objectives are to determine the effects of central infusions of a FGF21 mimetic (LY2405319) and a FGF21 antagonist (deltaN17) on metabolic rate, food intake, locomotor activity and body weight in fat and lean hamsters. Both compounds have been provided under the terms of a MTA by Eli Lilly. Metabolic responses will be compared to hamsters treated with FGF21 peripherally, and importantly in hamsters that are pair fed to match the food intake of the treated animals so that direct effects of manipulation of the FGF21 axis can be distinguished from indirect actions via altered caloric intake. Studies will be designed so that at the end of each experiment, key tissues (brain, brown fat, white fat, liver, bone) can be archived from the experimental animals to establish the actions of FGF21 on signal transduction pathways (ERK1/2) and known effector systems, for example UCP1 and deiodinase2 expression in brown fat. Analysis of these tissues using qPCR and Western blot analyses will form the bulk of practical work in year 3 of the project.