Function of brainstem brain-derived neurotrophic factor (Bdnf) in food choice

Obesity represents a major medical and economic challenge of the 21st century. The primary cause of obesity is the consumption of more food than the body requires, calories that are then stored as fat. An understanding of the biological mechanisms regulating food choice and meal size is essential to successful prevention of obesity. The brain represents the master coordinator of appetite, employing a number of interwoven neurological circuits to continually appraise and respond to changes in nutritional state. A principal node within this network is a brain chemical called brain derived neurotrophic factor (Bdnf), which is a powerful regulator of appetite and body weight. Therefore, a clear understanding of the precise mechanism through which Bdnf 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. To overcome this obstacle, we generated a powerful new means to discover the location of crucial sources of Bdnf responsible for communicating meal-related information, and how Bdnf, in turn, influences our decisions about what foods we choose to eat. We hypothesise that Bdnf within a brain region called the nucleus of the solitary tract controls appetite and food choice by directly sensing and responding to the nutrients in the food we eat. Furthermore, we hypothesise that the regular over-consumption of calorie dense foods disrupts Bdnf's detection of nutrients, which then facilitates over-eating. We will test these hypotheses using state of the art technology in this application and anticipate that the data generated will reveal an important component of the biological underpinnings of appetite, food choice and body weight, 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 energy homeostasis. Whilst genetic and pharmacological research have revealed that the secreted protein brain derived neurotrophic factor (Bdnf) is a principal regulator of appetite and body weight, the specific sources of Bdnf mediating these behavioural and physiological processes has not been defined. On the basis of our preliminary data, we hypothesise the Bdnf subpopulation within the nucleus of the solitary tract (NTS) to be a critical component of the brain appetitive network. We will test this hypothesis here by genetically inactivating Bdnf exclusively within the NTS and assessing food choice, meal patterning and body weight/fat. Further, we have generated a novel Bdnf-Cre mouse line that will allow the first reversible control via activation/inhibition of only NTS Bdnf neurons, which will illustrate their physiological functions in freely behaving mice in real time. Specifically, discrete NTS Bdnf cell chemogenetic manipulation, together with comprehensive metabolic phenotyping (including food choice, meal size, energy expenditure and body weight/fat), provides a mechanism to evaluate the physiological salience of brainstem Bdnf neurons in appetitive behaviour. Finally, by intercrossing our Bdnf-Cre line with a reporter line, we will perform the first targeted electrophysiological recordings from Bdnf cells to establish whether these neurons sense and respond to specific dietary nutrients. These data will offer important insight into the discrete neuronal circuits governing nutrient signalling, appetite and food choice. 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 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 of Nutrition and Health 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 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, 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 is the second largest cause of cancer, 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 Arena. Arena'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), a finding 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 Bdnf 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 Bdnf 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 well being and enhancing quality of life. The project therefore provides an excellent vehicle for increasing public engagement and understanding.