Bilateral BBSRC-SFI: The role of hypothalamic neuropeptide network in regulating tissue sizes in response to diet energy content and composition

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If you go on a diet to lose weight then you don't only lose body fat. You also lose muscle mass and your vital organs like your liver, heart and brain also shrink a little. If you put on weight however you generally put on disproportionately more fat tissue, but you may also deposit fat into your liver and muscles. It is thought by some scientists that this deposition of fat into the liver and muscle may be a primary reason why some people with obesity also develop type 2 diabetes. Another situation involving body composition changes is if you are unlucky enough to have a heart attack or develop a serious disorder like chronic kidney disease or cancer. An unfortunate side effect of these conditions in some people is that you may lose appetite and in these situations when you lose weight you lose lots of muscle as well as reduced vital organ sizes. These changes can have a major impact on quality of life of the chronically sick patient, and they greatly increase the risk of dying. Finally as we age some people go into a negative energy balance state where they also lose muscle mass over longer periods of time which leads to weakness and contributes to frailty which is a major risk factor for mortality in later life. At present we know very little about how the system that regulates these changes in our body composition actually works. We have some evidence that a small area of the brain that is known to regulate how hungry we are, called the hypothalamus, may play an important role in co-ordinating the responses of the individual tissues to overall changes in energy balance. The aim of this work is to find out the key genes in the hypothalamus that may be involved in this regulation. The first step in doing this is to explore how the global pattern of gene expression in this brain area changes when we perturb the system in different ways - giving different diets and restricting energy supply by different amounts. We will then be able to correlate the changes in the brain to the patterns of tissue use. To show that the genes are causally related to the tissue size changes we will manipulate the genes directly and then see how that alters the response to a change in energy balance. For example, from the correlations we may find that the expression of gene 'x' is strongly linked to the increased use of skeletal muscle when we are in negative energy balance. So we will knock that gene out and then see how not having this gene affects the muscle use. If, when we knock out the gene, there is no muscle loss, then we will know that the gene we manipulated has a direct effect on that part of the system. Our primary aim in the grant is to find the key genes that are involved in regulating the system. These genes might then become targets for the development of pharmaceuticals that might be able to affect our tissue utilisation patterns. For example it may be possible to use this information to develop drugs that can be given to patients with chronic diseases like cancer to prevent their weight loss. This would potentially have a large impact on both quality of life and mortality of chronically ill patients. Moreover, since we will be manipulating diets to find out how the system works this may also allow us to make dietary recommendations to achieve the same ends, both for chronically ill patients but also for people engaged in weight loss strategies to alleviate obesity. Ultimately we consider it may be possible to devise nutritional interventions that maximise fat loss and minimise loss of other tissues when dieting, and conversely prevent fat gain and maximise tissue recovery when a diet ends. This grant will provide the first steps towards making that happen.