IPA: Mechanisms that elicit weight loss with selective peptide agonism

We are currently living in an obesity epidemic which has huge health consequences for individuals and for the whole of society. Therefore, it is imperative that we investigate how our body regulates fat mass under normal and obese conditions, so that we might provide new avenues to educate or treat people suffering with excess body weight. Most treatments for obesity involve decreasing the amount of food we eat, either through dieting, pharmaceutical drugs or surgery. An alternative would be to increase the amount of energy we expend either by increasing exercise or by changing the balance between the fat we "store away" and the amount we "burn off." Our laboratories have had a long-standing interest in how the brain controls body weight. In particular, we have shown previously that brain cells, which produce a class of messenger called RFamides, can affect body weight quite dramatically. Some RFamides reduce food intake, while others increase energy expenditure, or do both. Recently, we have discovered that selective drugs which act on the receptors for RFamides can reduce body weight in obese mice, when the drugs are administered into the body, rather than into the brain. Very importantly, the drugs do not affect the amount of food the mice eat. Instead, they appear to affect the way fat is handled in the body. This is exciting because currently there are no safe treatments which have this effect. However, we do not know whether this is because the mice make less fat or burn more off. Nor do we know if the drugs have to get into the brain to have their effect, or whether they act directly on other organs, such as the liver or fat depots. To answer these questions, we will examine drugs which have different affinities for different RFamide receptors and measure their action on fat balance. We will breed mice which express special genes in specific cells of the brain. These mice are normally healthy, but we predict that they will become very fat if given a high-fat diet, similar with what is happening to people in the UK today. By using these mice, we will be able to pinpoint exactly where the drugs are having their action. In the future, this will allow us and our collaborators within the pharmaceutical industry to devise new treatments for obesity.

The prevailing obesity epidemic means it is imperative that we investigate how our body regulates fat mass under normal and obese conditions. Most current treatments for obesity involve decreasing energy intake, either through dieting, pharmaceutical drugs or surgery. An alternative would be a safe increase in fat handling and/or energy expenditure. Our laboratories have had a long-standing interest in how the brain controls body weight. In particular, we have shown previously that RFamide peptidergic neurones can affect body weight by reducing food intake, by increasing energy expenditure, or both. Recently, we have discovered that selective RFamide receptor agonists can reduce body weight in obese mice, when administered systemically. Importantly, these treatments do not affect food intake but, instead, affect energy expenditure and/or substrate utilisation. The mice display an immediate and long-lasting reduction in respiratory exchange ratio. This itself might reflect a decrease in de novo lipogenesis, an increase in lipid oxidation and/or an increase in adaptive thermogenesis. We hypothesise that the agonists gain access to the caudal brainstem to increase sympathetic outflow to metabolic tissues and alter lipid metabolism, but may also act directly on adipose tissues to reduce inflammation and increase insulin sensitivity. These possibilities will be investigated using both Cre-expressing and conditional receptor knock out mouse lines, combined with indirect calorimetry, remote radiotelemetry and channel rhodopsin-assisted circuit mapping.