Oxytocin pathways affecting metabolism

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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.