Oxytocin - a sweet hormone?

Obesity is an increasing problem in the UK. Obesity results from an imbalance between energy intake and energy expenditure, but there is no simple solution - the physiological, psychological, genetic and environmental factors that influence what we eat are complex, and different for different individuals, and we need to understand these better. One facet that is poorly understood is what controls the food choices we make - how much fat we eat, for example, and how much sugar. This isn't a simple matter of "taste" - our brains unconsciously monitor and regulate our consumption of particular components and direct future preferences.

One important brain mechanisms uses the neuropeptide oxytocin; its release is activated by sugar in the gut, but inhibited by fat. Oxytocin is released from a brain region called the hypothalamus, and it controls diverse aspects of appetite control and food choice.

One feature of the hypothalamus is how similar it is across different mammals, and for this reason, studies in mice and rats are powerfully predictive of hypothalamic functions in humans. This project will use laboratory rats to study how the oxytocin system regulates food choice. To do so we will use modern techniques that allow us to control the activity of oxytocin cells, and also that of the cells which are sensitive to oxytocin. This might help to develop new approaches to help people who have developed unhealthy eating habits that predispose them to diabetes, by "boosting" the systems in the brain that normally regulate the intake of specific nutrients, redirecting their food preferences away from sweet, energy-dense food.

This proposal addresses the role of hypothalamic oxytocin (OT) in the regulation of food choice. In rat models we will test whether gut-brain signalling, specifically the signalling systems activated by high-sugar foods, triggers dendritic release of OT to modulate behaviorally-relevant neuronal circuits in the ventromedial nucleus of the hypothalamus (VMN). The VMN expresses abundant OT receptors, is a major satiety centre, and is involved in directing attention to specific motivated behaviors. These experiments are important to understand how peripheral signals related to macronutrient intake are integrated by the hypothalamic control centres and regulate food choice. They will involve measuring OT release by microdialysis in vivo, in vivo electrophysiology, and pharmacogenetic approaches to control cells expressing the OT receptor and those that release OT. It will focus on magnocellular OT neurons, these release large amounts of OT from their dendrites, and it is this that is likely to be relevant to actions at the VMN, which contains few if any OT-containing fibres. Thus, OT is likely to have "neurohormonal" actions at this site. A focus will be on "priming" of dendritic release; priming is a mechanism whereby certain signal to OT cells can affect their subsequent availability for activity-dependent release. Thus, priming can produce a delayed but prolonged enhancement of dendritic secretion. This may help explain how an acute stimulus (intake of a particular food) can result in longer term changes that produce a change in subsequent behavior (food preference). The project will contribute to a better understanding of the physiological regulation of dendritic OT release, address the question of whether diffusional transmission of OT is a major mediator of communication between neurons, and provide evidence for food choice-related behavioral effects mediated by specific hypothalamic neurons.

The proposal links with the BBSRC Initiative of "Nutrition for Health" to understand how foods, nutrients and whole diets influence cellular processes, how these influences affect overall health outcomes. By the end of the grant we will have established whether gut-brain communication triggers central oxytocin release and how this modulates food choice. Administration of oxytocin analogues crossing the blood-brain barrier might be a future therapeutic approach to improve food choice. We expect the approaches used and data generated in this project to have an impact via several routes:

1. Academic community. Our previous work has led to high impact publications and this has given us a high profile in the academic community. Disseminating research outcomes is a priority for this project. In the last two years, we gave invited presentations at national and international conferences, including EB (USA), BES (UK), ECE (Netherlands), SBN (USA), IUPS (UK), SSIB (USA), Endo (USA), the Society for Nutrition (Dublin), the Japan Endocrine Society, the Turkish Neuroscience Society, and the Royal Society of Medicine (London). We expect that there will be ample opportunities for dissemination through invited as well as volunteered contributions to major conferences, and manuscripts submitted to high-profile journals.

2. The public. We will accompany published papers with targeted press releases, using the University Press Office, and also will target science journalists and use social media channels. It is important that the outcomes of this project are effectively disseminated not only to scientific peers, but also to the general public to help explain how public investment in basic science brings benefits to health and well-being. We have been extremely active in outreach activities, including public lectures, media appearances, science festivals, articles in the popular press, and on-line briefings and education, including Frontiers for Young Minds. ML and JM edit Neuroendocrine Briefings, a series of articles for the lay reader widely disseminated in print and online and through scientific societies, and we expect to contribute a Briefing on the topic of this project. JM designed and delivered a massive open online course called "Understanding Obesity" that has had >18,000 sign-ups from 175 countries to date. We anticipate maintaining this level of engagement throughout the project.

3. Commercial and industrial partners. The project has potentially important translational implications, and these will be managed with the support of Edinburgh Research and Innovation (http://www.research-innovation.ed.ac.uk/), which has extensive expertise in the protection of intellectual property arising from grant-funded research, and in fostering translational outcomes. We have good links with pharmaceutical industry if partnership seems appropriate: GL has collaborated with Merck & Co for many years.

4. Policy makers. Interest is increasing in understanding the determinants of food choice from the perspective of policy. In recent years, we have established collaborations with behavioural economists and policy design experts working on the Nudge-it project. We will foster these links across the project.

5. Training opportunities. Training postgraduate and postdoctoral researchers is a key activity in the applicants' labs. In the past ten years the applicants have supervised 10 PhD and 8 MSc students, as well as many BSc Hons laboratory projects and summer scholarships. We will offer these through the project and will apply for externally-funded PhD scholarships to complement the main objectives of this project. The named postdoc and technician will be trained in in vivo experimental approaches including electrophysiology and pharmacogenetics. Research staff development is also supported by Edinburgh University's Institute for Academic Development, and the named research staff will be encouraged to participate in relevant training.