Visualising homeostatic and hedonistic appetite in rats using functional MRI.

The biggest health issue facing the UK is the increasing prevalence of obesity (excess storage of fat). We live in a society where energy-rich food is generally cheap and easily available, and where we have very sedentary life styles. Therefore, our natural ability to regulate our body weight is being undermined. Obese and even moderately-overweight individuals have greatly increased chances of developing diabetes, vascular diseases and cancer: making the treatment of obesity-related diseases an enormous burden on the National Health Service and similar agencies around the world. Many organs, including fat tissue, the liver and the pancreas, interact to regulate both our body weight and the availability of the fuels that we need for our bodies to function normally. However, it is the brain that co-ordinates this regulation. Thus, we need to understand how the brain detects and responds to all the different sources of information that ultimately determine how much we eat and how much body fat that we store. It is not surprising that, due to the complexity of the brain, we still have only a limited understanding of how this organ carries out the function. The brain has complex circuits that act to try and balance our food intake to our energy needs. Unfortunately, in humans appetite is controlled less by physiological requirements and more by other factors such as what time of the day it is, if we like or dislike the food that is available or if we are eating with other people. One of the biggest problems with controlling our eating is that it is a pleasurable and sociable experience. Thus, we tend to choose sweet or fatty foods / the worst kind if we wish to reduce our weight / and we tend to eat even if when we are replete. We will develop cutting-edge technology to image the brain's response to a number of different stimuli that affect appetite. Thus, using a powerful magnetic resonance imaging (MRI) machine, similar to that used in everyday clinical diagnosis, we will determine which part of a rat's brain is important for detecting and responding to these signals. We will test a number of stimuli that increase appetite in order to assess how different parts of the brain interact. As the rat is anaesthetised throughout the imaging, the stimuli will artificially mimic the feelings of hunger and the pleasure of eating. We will use this information to understand normal brain functioning, how this may differ with the development of obesity and how treatments may be able to help. This knowledge will benefit academics, health professionals and the pharmaceutical industry, enabling them to improve care and to develop drugs for problems as diverse as obesity and anorexia.

The biggest healthcare issue facing the National Health Service is the increasing prevalence of obesity (excess storage of fat) and the related morbidities of diabetes, cardiovascular disease and cancer. As appetite and body weight regulation is co-ordinated by the nervous system, there is a growing need to understand brain functioning and how intervention might be achieved to treat not only obesity, but also appetite loss and wasting due to chronic illness and psychological problems such as anorexia nervosa and bulimia. To date research has focussed on the hypothalamus, the key integratory region for homeostasis, and the brainstem, important in detecting satiety and nutrient levels. However, it is apparent that appetite and body weight control is intimately linked to other regulatory mechanisms, behaviour and emotions: an individual has homeostatic, hedonistic and social drives to eat. In order to control appetite in humans we need to understand more about higher cognitive functions, such as decision-making and the motivation to eat. Increasingly, over eating and the consequent obesity is compared with drug addiction. Thus, we need to understand how reward circuitry is engaged during the process of eating. We are developing the use of pharmacological magnetic resonance imaging (pMRI) of rat brain to help understand brain function related to appetite. Using systemic injection of the drug, mCPP, as a proof-of-concept in work leading up to this project, we have shown that a 7-Tesla magnet provides excellent spatial resolution of the rodent brain using the BOLD technique for functional imaging. We will now test a number of stimuli that are known to regulate appetite either homeostatically or hedonistically using pMRI and complementary behavioural and functional gene mapping studies. We will build a catalogue of pMRI activity motifs to enable evaluation of the specific and possibly non-specific effects of other, novel regulators of appetite. Within this project, also we will develop our techniques to lay the foundations for further basic and clinical research.