A thermogenic circuit that maintains sensitivity to leptin in obesity

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We are experiencing an epidemic in the prevalence of obesity; a disease which develops after the body's protective systems become overwhelmed in an environment which is full of sugary and fatty foods. Normally when we put weight on, our fat tissues release a hormone called leptin, that travels to the brain to help us to reduce eating, but also to increase the amount of energy we burn off by a process called thermogenesis (literally, heat production). One of the reasons we find it difficult to lose the extra weight is because the parts of the brain that control eating, become resistant to the effects of leptin, so it no longer works. We have learned a lot about the part of the brain controlling eating, because we have identified the types of nerve cells there which possess the capability to respond to leptin (i.e. those that have receptors for the hormone). Importantly, a different part of the brain controls the thermogenic response to leptin, and the cells here do not become resistant to leptin. This makes them of great interest to scientists and doctors wishing to find way of reducing the obesity problem. Unfortunately, until now we did not know what types of cells these were.In our preliminary work leading up to this project, we have now identified three different cell types which all appear to play a role in thermogenesis. However, only one of them has leptin receptors. The cells that are directly sensitive to leptin contain a signaling chemical called PrRP. Our hypothesis is that the PrRP-containing nerves control the other cell types and also the messages from the brain to the organs that actually cause thermogenesis. We have bred different types of mice which will allow us to study the different cell types very carefully. We will be able to see how they respond to leptin, how they make connections, and how they communicate with each other. Perhaps most excitingly, for the first time ever, we can switch on or off the different nerves selectively, just by giving the mice a harmless drug. Thus, we can switch on the nerves to drive thermogenesis or switch the nerves off to stop them responding to leptin.A complete understanding of the different types of nerves will allow the selective targeting of either the nerves themselves or their connections with the organs that control thermogenesis. This knowledge will help the discovery of drugs which, one day, could help prevent the development of obesity.