Defining the underpinnings of Neuropeptide Y (NPY)'s control of hunger and body fat

More than 60% of people in the UK are overweight or obese. The primary cause of excess body weight is the consumption of more food than the body requires, calories that are then stored in fat. The reason this is important is because poor diet and excess body fat commonly has a detrimental impact on health. The focus of this application is clarifying the biology behind food choice (why do we prefer cake to cabbage?), meal size and body fat accumulation. The brain represents the master coordinator of appetite, employing discrete interwoven circuits to continually appraise and respond to changes in energy availability. A principal node within this network is a brain chemical called brain Neuropeptide Y (Npy), which is a powerful hunger hormone. Therefore, a clear understanding of the precise mechanism through which Npy modulates how much food we eat and the types of food we choose is of intense interest. However, discoveries in this direction have been hindered by a lack of precise tools. Recent technological advances now provide a means to overcome this obstacle, affording a way to discover the location of crucial sources of the brain's Npy that influence our decisions about what foods we choose to eat and whether these calories are used or stored in body fat. We think that Npy within a brain region called the nucleus of the solitary tract performs this essential function. We believe Npy in this region does two things to make sure that we have enough calories on board. One, it increases hunger, food intake and a preference for high calorie foods. And two, it tells the body to store calories in fat so that we have a supply of energy later if we need it. Data generated thus far support this idea. Using a combination of state of the art techniques, we will test the function of this special source of Npy in hunger and body fat in the proposed research programme. This work is important because we believe we have found an essential way that the brain controls hunger and food choice. Moreover, we think we have uncovered a new way that the brain talks directly to body fat, telling it to either store or expend calories. We anticipate that these studies will provide fundamental insight into the biological underpinnings of appetite, food choice, body weight and body fat, findings relevant to the prevention and treatment of obesity.

The national prevalence of obesity emphasises the need for a greater understanding of the physiological mechanisms underlying intake and storage. Whilst genetic and pharmacological research have revealed that Neuropeptide Y (Npy) is a principal regulator of hunger and body weight, the specific sources of Npy mediating these behavioural and physiological processes has not been fully defined. On the basis of our preliminary data, we hypothesise the Npy subpopulation within the nucleus of the solitary tract (NTS) to be a critical component of the brain appetitive network that also initiates a programme of energy storage in adipose tissue by inhibiting lipolysis. We will test this hypothesis here by performing the first targeted manipulation of Npy NTS activity (activate/inactivate) and perform metabolic phenotyping (including food choice, meal size, energy expenditure and body weight/fat characterisation) to evaluate the physiological salience of Npy NTS in energy balance, body weight and energy storage in adipose tissue. We will also examine the brain circuit through which these effects are achieved by stimulating or inhibiting Npy NTS release specifically within the paraventricular nucleus of the hypothalamus (PVH) and employing CRISPR/Cas9 to knockdown the Npy 5 receptor exclusively within the PVH (Y5R PVH). These studies have the potential to clarify a new circuit through which the brain controls hunger and food choice. We also expect the research here to establish a novel brain circuit directly influencing energy storage in adipose tissue. Thereby, this programme of research will offer important insight into the discrete neuronal circuits governing appetite, food choice, body weight and body fat accumulation. Given the pervasiveness of obesity within the global community and the resulting socio-medical ramifications, deciphering the neuronal circuits governing the physiological control of ingestive behaviour and body fat is essential.

Academic impact
Nutrition and health is a continually expanding area of research, in which the UK has arguably been at the forefront. In particular, the host environment, the Rowett Institute has been producing ground-breaking research in this area for over a century. Nutrition and obesity research are multi-disciplinary fields that encompasses neurobiology, physiology, pharmacology, genetics, the food sector and public health. This proposal therefore, has the potential to make a broad and significant academic impact, both within the UK and internationally, by furthering our understanding of the molecular mechanisms underlying ingestive behaviour, body fat accumulation and metabolic health/disease. In addition to advancing knowledge, the proposed research will provide important capacity building by training the field's scientific leaders of tomorrow to encourage the maintenance of the UK's leading position in this area of scientific research. This will provide the potential for expansion of our research findings into other relevant animal models and incorporation in broader neuroscience, genome editing, chemogenetic, pharmacological and genetic approaches. The research will also provide opportunities for improving teaching and learning of undergraduate and postgraduate students through seminars and research projects.

Economic and societal impacts
Obesity is a major health problem in the UK, accelerating death and poor diet-related ill health costs the UK £5.8 billion every year. Obesity substantially increases the risk of heart disease, type 2 diabetes, and many other medical diseases. Currently, only one drug is approved for long term obesity treatment in the UK, Ali, which is a lipase inhibitor. Given the prevalence of obesity worldwide and its health, societal, and economic implications, new treatments are a health imperative. In previous research, we pursued this conundrum by investigating the therapeutic mechanism of obesity medications withdrawn from clinical use due to off-target effects. We determined that the therapeutic mechanism of 5-HT medications is via activation of a discrete class of receptors 5-HT2Cs, expressed on a chemically defined population of neurons, pro-opiomelanocortin (POMC) (e.g. Heisler et al., Science 2002; Xu et al., Neuron 2008; Xu et al., J. Neuroscience 2010). This work further stimulated and supported drug discovery efforts for 5-HT2C receptor agonists at multiple pharmaceutical companies, including Eisai. Eisai's compound, lorcaserin, was approved by the USA FDA and launched for obesity treatment in 2013. Further, we identified the 5-HT2C receptor is a mechanistically novel target for the treatment for type 2 diabetes (Zhou et al., Cell Metabolism 2007; Burke et al., Molecular Metabolism in press), a finding now replicated in patient populations. An advantage of the new chemogenetic technology that we are employing in this application is both regional and temporal refinement. We speculate that directly targeting brainstem Npy cells will provide an effective new pharmacological target for the treatment of obesity. Therefore, there may be opportunities for the commercialisation of new diagnostics (identifying individuals at risk of obesity) and therapeutics (targeting specific Npy neurons). The proposed research may inform and benefit the pharmaceutical sector through access to new knowledge, technology development and databases. Thus, it has the potential to enhance the knowledge economy and economic competitiveness of the UK. The research is also readily accessible to the general public, because of its immediate relevance to improving health and wellbeing and enhancing quality of life. The project therefore provides an excellent vehicle for increasing public engagement and understanding.