Oxytocin pathways affecting metabolism

Currently over a quarter of UK adults are obese, leading to major problems with diabetes and cardiovascular disease, the treatment of which puts immense strain on the NHS. As obesity develops, the brain becomes resistant to feedback signals from the body which normally indicate that the person is overweight. As a consequence the individual will tend to overeat even when full. To reverse obesity, treatments will be required to bypass this resistance; but it is difficult to design drugs which can access the brain and that do not have unwanted side effects. One target being investigated by a number of commercial and academic groups is the oxytocin system. It has been known for many years that oxytocin is released from the brain to control child birth and breast feeding. However, oxytocin released within the brain can mediate social bonding, for example between a mother and her baby. It seems that oxytocin within the brain does, in fact, affect many different types of behaviour. Humans with low numbers of oxytocin-producing cells (Prader-Willi Syndrome) are obese and have powerful appetites. Recent experiments in obese animal models have shown that long-term administration of oxytocin decreases food intake and increases energy expenditure, even though the animals are resistant to the body's feedback signals. Importantly, studies in humans, where oxytocin accesses the brain directly via an intranasal spray, can reduce food cravings, eating and body weight. While it looks like a very promising treatment, little is known about how oxytocin brings about these beneficial effects. Lessons have been learned from previous obesity treatments that have proven dangerous because of unseen side effects. We predict that oxytocin is effective and safe because it bypasses the body's feedback signals and mimics the natural cyclical satiety signals that we normally experience in between meals. We will provide evidence that the activity of oxytocin cells (neurones) reduce appetite without causing adverse effects, while at the same time increasing energy expenditure and fat break down. We will demonstrate that these actions of oxytocin are mediated by distinct pathways in the brain.
There is a population of oxytocin neurones in a small area of the brain, called the paraventricular nucleus, which integrate signals from the body and then activate a number of different outputs which will affect body weight either directly or indirectly. However, there are other populations of oxytocin neurone, so we need to be sure we are studying the correct cells. We have developed transgenic mice in which we can visualise and manipulate oxytocin neurones. Thus, we can record the electrical activity of these neurones and look to see where they make connections elsewhere in the brain. By making different populations express a "designer receptor", we can then activate them selectively in normally behaving mice, thus establishing the importance of the paraventricular oxytocin neurones. These neurones project to distinct parts of the brain to affect different aspects of metabolism. A connection with an area called the BNST has an effect on motivational behaviour. Thus, we hypothesise activating this connection will reduce hunger naturally (and not by causing an aversive response, such as sickness). A second projection goes to the brainstem, where signals controlling the gut are integrated. Acting here, we believe oxytocin slows down the rate at which the stomach releases food into the gut. This delayed emptying increases feelings of fullness and extends the period of satiety between meals. Finally, a third projection goes directly to the spinal cord. Here oxytocin acts on outputs to peripheral tissues, including fat depots. Increased activity in white adipose tissue, where we store excess energy, leads to a breakdown of fat. Likewise, higher activity in a specialised tissue, called brown adipose, increases energy expenditure, so that more calories are burned.

As obesity develops, the brain becomes resistant to signals which normally balance body weight, such as adipose-derived leptin. Reversing obesity will require bypassing this resistance, by identifying accessible targets downstream of leptin signalling. One such target being investigated is the oxytocinergic system. Chronic administration of oxytocin (Oxt) decreases food intake and increases energy expenditure (EE) in leptin-resistant models. Intranasal Oxt, which can access the brain, has acute effects on food intake, reward and craving in humans, and eight weeks treatment is reported to reduce body weight in obese patients. We will provide evidence that Oxt neurones can reduce appetite without causing adverse effects, while at the same time increasing both EE and peripheral lipolysis. We will use the latest techniques of chemo- and optogenetics to demonstrate that these major actions of Oxt are mediated by distinct central pathways.
We predict that Oxt-receptive, OxtrBNST cells, form local inhibitory connections with GABA BNST to LH neurones, which have been shown previously to cause a strong feeding response, and with GABA BNST to VTA neurones which increase reward. Activation of either pathway can induce place preference and/or self-stimulation, indicating an increase in motivational valence. Thus, the OxtPVH to OxtrBNST to GABABNST pathway would inhibit BNST outputs to both the lateral hypothalamus and ventral tegmental area and decrease the motivation to eat (i.e. reduce hunger). Concurrently, OxtPVH neurones projecting to the brainstem would inhibit gastric emptying via the parasympathetic system and this would indirectly reduce food intake. Thus, the OxtPVH to OxtrNTS to AChDMX pathway induces satiation and increases satiety. Finally, a direct innervation of sympathetic neurones in the intermediolateral spinal cord (OxtPVH to AChIML) would induce thermogenesis in brown adipose tissue (leading to increased EE) and enhance lipolysis in white adipose tissue.

In 2010, 26% of adults and 16% of children in the UK were classed as obese. A further 42% of men and 32% of women were overweight. Co-morbidities related to obesity, such as diabetes, heart disease and kidney disorders, create a massive public health problem, and are projected to cost the NHS £9.7 billion per annum by 2050. It is a widely held view that the current epidemic in human obesity is due to the fact that over-weight people, even though they have adequate energy stored in their bodies, are still driven to over consume because they become resistant to anorectic signals. In order to understand new interventions to treat obesity safely, we will separate different aspects of appetitive behaviour, the pathways involved and the factors that regulate them. Our laboratory is well placed to make a major impact on understanding the brain networks that control energy intake and expenditure, as we have available the necessary models, tools and expertise. Our findings will be disseminated to our academic and clinical colleagues at international conferences and by publication in high-impact journals during the grant's duration.
The potential global market for obesity drugs is over $100 billion. This project will guide future development of a new class of drugs for the regulation of metabolism. The PI has been involved previously in successful collaborative projects with a number of industrial partners, providing evidence for several novel targets for drug development that has underpinned programmes by AstraZeneca, Eli Lilly, Servier and Novo Nordisk. We will use the project to further develop industrial collaborations, which the PI has done successfully previously with the award of three Industrial Partnership Awards. Any intellectual property derived from this project will belong to the applicant and The University of Manchester. Any future contract negotiations will be carried out through the University's Intellectual Property company, UMI3 Ltd.
The PI will continue to provide consultations to different bodies regarding obesity research (in the past with commercial companies, funding agencies, The Royal Society and with The Department for Business, Innovation and Skills), which will affect future funding policy. During the lifetime of the grant, the basic research will be discussed at meetings organised by the Child Health Research Network, the Diabetes and Obesity Research Network and the Association for the Study of Obesity. These annual meetings are forums for basic researchers, psychologists, clinicians, community nurses and other health professionals, patient group representatives and policy makers.
This project will provide strong training in both in vivo skills and specialist techniques in electrophysiology, chemogenetics and optogenetics, metabolic and behavioural research. In the last twelve years, the applicant has supervised 12 PhD students, 21 Masters students and 10 PDRAs, the majority of whom have remained in science (some have their own independent research groups and others have moved into the commercial sector). The applicant is external examiner on another University's integrative Masters course and regularly examines PhD theses. He directs a cross-University Integrative Mammalian Biology initiative to promote and expand research and training in in vivo biology. This problematic area is crucial to the UK economy and to the ambitions of Manchester to be a world-leading university.