Resolving a novel brain circuit controlling appetite and body weight

Here is a startling statistic - more than half the people in the UK are overweight or obese. This is a relatively recent epidemic that is getting worse. Excess body fat primarily results from eating more food than the body requires, calories that are then stored as fat. My research is aimed at understanding what makes us hungry and full and how we can use this information to develop new medications to treat obesity. My second aim is to provide an understanding of obesity that might offer novel strategies for future treatments. According to Dame Sally Davies, Chief Medical Officer for England, obesity is the biggest threat to health and the health of future generations. Obesity increases the risk of developing major illnesses such as type 2 diabetes, cardiovascular disease, cancer and numerous other conditions and it is associated with a reduction in lifespan by approximately 8 years. The objectives of my proposal therefore address a critical health challenge.
Dieting should work, but it is not having an impact on the weight and health of the nation; 95% of people who lose weight gain it back. What is needed are multiple approaches to combat this widespread epidemic and my research is focused on the development of new medications.

Surprisingly, it is the brain that rules our appetite. Key regions of the brain are responsible for receiving and processing meal information to maintain the equilibrium between hunger and fullness, and to achieve this, specialized nerve cells are wired together in mind boggling networks within our brain. Following a meal, the gut sends chemical messengers into these networks about how much food has been eaten. These messengers activate particular cells in the brain that signal to other brain regions to trigger a decision about whether we have had enough food. The goal of my research is to understand this cross-talk and to decode how hunger and satiety information is passed on between different regions of the brain. I study a brain region called the nucleus of the solitary tract (NTS) because this region acts as a gateway between the gut and the brain, integrating meal-related information and funneling it to the right brain regions so a decision can be made.
What happens if more food than the body requires is regularly consumed? Not unlike tolerance to alcohol or a medication, it is possible that the NTS develops a kind of tolerance to nutrient signals and it takes more food for the brain to tell us that we are full. To test this hypothesis, I will turn off specific NTS nerve cells to make them unable to receive and pass on meal-related information and measure food intake and body weight. The aim of these studies is to understand whether such a fault in the system is one of the causes underlying the development of obesity and associated metabolic diseases.
It is likely that if we learn more about how the gut and brain communicate, we will be able to send these type of messages to the brain with a medication to reduce appetite and improve obesity. To learn the language of gut-brain communication, we first need to decode the words: the chemicals that these cells use to communicate with each other. My research aims to screen the chemical content of a small group of NTS nerve cells that control appetite to help develop new medications.
Another aspect of my research is creating a map of the appetite networks in the brain, like a road atlas. I will use techniques that colour specific brain circuits relying meal-related information. I will also turn these circuits on and off on demand and measure food intake. These studies will allow us to understand which part of the network is crucial for appetite regulation.

Overall, I aim to decode the function of a group of nerve cells, clarifying the chemicals they make, and the networks they build within our brains to control appetite - an area of knowledge critical to our understanding and treating the obesity epidemic and improving human health.

Obesity has emerged as a primary healthcare challenge of the 21st century because of its prevalence, burden on human health/NHS and the paucity of effective medications. I recently discovered that the activation of a specific subset of cells within the nucleus of the solitary tract that synthesise cholecystokinin (NTS-CCK) and potently reduce food intake and body weight. Here I propose to extend this work by dissecting the discrete metabolic NTS-CCK network at the genetic, anatomical and behavioural level, and evaluating its therapeutic potential for the treatment of obesity.

To achieve this, I will capitalise on the selectivity afforded by new technology for cell-specific activity manipulation and visualisation. To reveal specific NTS-CCK circuits modulating appetitive behaviour, I will rapidly and reversibly control NTS-CCK axon terminals using in vivo optogenetics. I will clarify the structural organisation of NTS-CCK circuits controlling appetite using Rabies-based retrograde labelling. Furthermore, I will characterise the transcriptional signature of appetite suppressing NTS-CCK neurons using RNASeq. To study the temporal dynamics by which signals of nutritional state recruit the NTS-CCK neurons, I will perform optical recording of their activity using in vivo calcium photometry. Finally, I will test the necessity of NTS-CCK neurotransmission for the maintenance of energy balance and how the lack of this circuitry impinges on the development and progression of diet-induced obesity and metabolic-like syndrome by site- and cell-specific ablation of NTS-CCK neurons.

I anticipate that the proposed research will generate an evidence base for a novel and distinct circuit critically transmitting information about nutritional status to modulate energy balance and body weight, a circuit that has a strong translational potential for the treatment of obesity.

My CDA objectives are to:
1. Contribute to the economic competitiveness of the UK through enhancement of researcher career development.
The MRC CDA will be fundamental in furthering and consolidating my research and translational skill set and establishing my independent research group. This CDA award comes at an exciting time for the host institute. Following a strategic investment of £40m for the construction of new research facilities, the Rowett Institute of Nutrition and Health (RINH) has now relocated into its new purpose-built building for nutrition and health research. This infrastructural advancement will have a significant impact on the progression of my career, as bespoke laboratory, space and state-of-the-art facilities are now available for the establishment of new research teams. Furthermore, the College of Life Sciences and Medicine at the University of Aberdeen will fund a 4 year PhD studentship and a 5 year Research Assistant (25% effort) to catalyse my CDA research, affording me the immediate opportunity to train young scientists in the UK and start building and a research team.

2. Establish links with clinicians with a view to integrating and/or translating my novel work into potential diagnostic and therapeutic tools.
The MRC CDA project will entail fundamental research important for our understanding of appetite regulation, a subject highly relevant to public health and medicine and a mission of the host Institute, the RINH. The RINH is an optimal environment for the CDA research and the establishment of my independent laboratory because of the opportunities to forge new collaborations with my Human Nutrition Unit colleagues within the RINH and The Centre for Healthcare Randomised Trials (CHaRT) colleagues in the adjacent building, collaborations that provide a tractable platform for the translation of my CDA research to humans

3. Investigate the potential commercial exploitation of the research outcomes.
I anticipate that my studies may provide novel therapeutic targets of interest to the industrial sector seeking to develop new medications for obesity and type 2 diabetes. I will seek advise from the Kosterlitz Centre for Therapeutics at the University of Aberdeen, an organisation that provides links between academics, industrial partners and the business sector. This will ensure that commercial opportunities arising from my work will be appropriately explored, protected and exploited (see Exploitation section).

4. Promote greater public understanding of science through public engagement activities.
The University of Aberdeen has a dedicated Public Engagement Research Unit (PERU) that will facilitate the public engagement (PE) of my MRC CDA research and augment my translational training. During the CDA, I will participate in the active Cafe Scientifique program and the annual TechFest and other activities (http://www.abdn.ac.uk/engage/public/research-interest-group-147.php). Additional mechanisms of PE that I will exploit are Faculty of 1000, which has public outreach activities in which I am actively participating, and web-based mechanisms of PE (e.g. websites, blogs, Twitter). Key scientific findings may also be publicised in press releases via the University of Aberdeen's Press Office, where appropriate, ensuring that my results are effectively broadcast and easily accessible. My objective is to define a mechanism by which the brain processes meal information - a topic regularly of interest to the general public given that 1 out of 3 children and more than 1 out of 2 adults are overweight or obese in the UK. Therefore, the development of new therapeutic strategies and a greater awareness of the impact of nutrition on health will ultimately be of benefit to public health.