Defining mechanisms through which neuropeptide Y drives hunger and body weight

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In recent decades obesity has become increasingly common around the world and this has led to significant and growing problems for health systems and societies globally. In terms of physical health, obesity increases the risk of heart disease, diabetes, cancer and associated complications. The main driver for obesity is eating more food than our bodies require, and the extra calories get stored as body fat. Thus, to be able to tackle obesity and its complications it is essential to understand how hunger and fullness are sensed in the brain. More than half a century ago, researchers discovered a part of the brain that is essential for controlling hunger, a region called the lateral hypothalamus. Despite this long-standing knowledge, it still is not known how this brain region fundamentally controls appetite and body weight. Thus far, the majority of attention has focused on brain chemicals made in this region called orexin-hypocretin and melanin concentrating hormone (MCH). However, what has not yet been investigated is a principal regulator of hunger called neuropeptide Y (NPY). This small protein made in several regions of our brain produces a profound increase in hunger, much greater than orexin-hypocretin or MCH. Historically, efforts have focussed on a subset of NPY, agouti-related protein and GABA co-expressing cells in another hypothalamic brain region, the arcuate nucleus. It has been subsequently revealed that NPY made in these cells is not the main driver of hunger. Thus, it is likely that NPY in other brain regions largely contributes to its vital effect on appetite. Of these, a group of NPY cells in the lateral hypothalamus (LHA(NPY)) is particularly interesting because these cells are able to detect changes in sugar (glucose) levels in their local environment. It is likely that this ability to detect glucose helps the brain evaluate whether we need food and react accordingly.In this project I will test whether NPY, a major hunger stimulator made in the key hunger brain region the LHA, is an important way that hunger and body weight are controlled. The project aims to answer these questions:(1) How are LHA(NPY) cells regulated? Previous research and pilot data provide compelling evidence that LHA(NPY) cells detect and respond to fluctuations in sugar. I will investigate how LHA(NPY) cells respond to nutrients and to different food cues, and how these signals directly shape the activity of LHA(NPY) cells.(2) Are LHA(NPY) cells able to drive food intake and promote obesity? There is evidence in humans and in animals that NPY is critical for appetite and body weight, but it is less clear what the particular contribution from LHA(NPY) cells is. To answer this question, I will experimentally activate LHA(NPY) cells and investigate if this leads to short term and/or long term increase in food intake, and whether LHA(NPY) overactivity leads to obesity.(3) Is it possible to prevent obesity by inactivating LHA(NPY) cells? Because NPY potently stimulates appetite, it is likely that obesity can be prevented by selectively inactivating the cells in the LHA that make this protein. Pilot studies indicate that this is indeed the case. Additional experiments will confirm and expand these initial studies to evaluate how effective is LHA(NPY) inactivation at preventing obesity.This project aims to discover how the brain controls the types of food that we choose to eat, how much we eat, and how that affects body weight. In discovering this, it will bring us closer to being able to find new medications to dampen our urge to over-eat and thus reduce the growing burden of obesity on our health systems and societies.