The human body responds to stress by producing a set of stress hormones (POMC, ACTH and glucocorticoids) which have multiple actions, but primarily increase factors which fuel our body to help it respond to stress. However, long term (chronic) stress is bad for us, and we believe this is because there are subtle changes in stress hormones, which increase the risk of diabetes and heart disease. We are working on ways to measure these subtle changes in stress hormones in models of obesity and diabetes and in different groups of patients. Stress hormones can also affect the networks in the brain that regulate food intake and energy balance. We are studying how this goes wrong in obesity and diabetes. We are also investigating how undernourishment in pregnancy affects these networks in the baby’s brain so that they are more likely to become obese as adults. Some cancers can also secrete hormones. In small cell lung cancer, the precursor protein from which ACTH is produced, proopiomelanocortin (POMC), is expressed and released into the blood. We are developing techniques that utilise this secreted POMC in the monitoring of tumour progression and response to treatment.

Role of glucocorticoids in diabetes and obesity

Many people take steroids (glucocorticoids) for a range of inflammatory conditions and autoimmune disorders. However although they are extremely beneficial they do have a number of side-effects and chronic treatment with glucocorticoids can lead to type 2 diabetes.

This is not surprising as endogenously produced glucocorticoids such as cortisol have a range of metabolic effects. While quite a lot is known about their actions on peripheral organs such as the liver relatively little is known about their actions in the hypothalamus. This is surprising as they are known to regulate both POMC gene expression and therefore αMSH production and AgRP synthesis.

As a group we are interested in examining how chronic glucocorticoid treatment acts on the neuropeptide networks in the hypothalamus to cause metabolic abnormalities. We use a mouse model where we treat with corticosterone in the drinking water and after 24 hours the mice increase their food intake and by three weeks they have an increased body weight and insulin resistance with some tendency to hyperglycaemia.

Programming of energy balance: role of maternal diet and stress hormones

We are interested in understanding how undernutrition and overnutrition during pregnancy affects the baby leading to an increased chance of developing obesity and diabetes. We have shown that this alters the epigenetic status of genes involved in the regulation of appetite and HPA axis function. Our work was aimed at determining how these programmed changes occur ( former collaboration with Prof. Frank Bloomfield in New Zealand and Prof. John Challis in Canada).

Assessment of Stress Hormones

POMC processing

Pro-opiomelanocortin (POMC) is the precursor of the hormone adrenocorticotrophin (ACTH), and processing varies in different tissues. We study mechanisms regulating production of active hormones and utilise a panel of highly sensitive antibodies, generated by the group, to detect the different products of POMC. This allows us to determine which peptides are being produced by different cell types and in different disease states. 

POMC secretion by tumours

We have previously shown that many tumours, but particularly small cell lung cancer (SCLC), express POMC and release it into the blood. SCLC is an aggressive neuroendocrine tumour that has a poor prognosis. Our group is interested in investigating POMC as a novel biomarker for SCLC using xenograft models (A and B below). There is evidence to show that SCLC has a dual phenotype exhibiting both neuroendocrine and epithelial markers (C). We are interested in the importance of this dual phenotype during metastasis and whether SCLC cell lines and xenografts show heterogeneity of these markers. More recently we have started investigating the significance of the heterogeneity in resistance to chemotherapy and radiotherapy.

A. SCLC xenograft tumour stained for POMC (brown). Nuclei are stained with blue. B. Circulating POMC levels mirrors tumour growth in mice with xenografts.

• Molecular Endocrinology techniques including transfection analysis, reporter gene assays
• Mouse models of chronic glucocorticoid treatment
• Immunoassay development and immunocytochemistry
• Monoclonal antibody production
• Purification and characterisation of peptides by immunoaffinity analysis, HPLC and western blotting
• Characterisation of human small cell lung cancer cell lines, cloning and stable transfection analysis

• Chair MRC Doctoral Training Grants Panel 2009-2011
• Chair MRC Capacity Building Studentships Panel 2008-2011
• Panel member MRC Training & Careers Group 2010-2011
• Society for Endocrinology
• The Endocrine Society (USA)
• British Society for Neuroendocrinology

• Dr Erika Harno

• Dr Charlotte Sefton

• Tiffany-Jayne Allen

• Leanne Walker

We participate in events with high school children where they come from all over the North West of England  to the University to learn more about science. This is a highly interactive format during which our group runs a “Diagnosing diabetes” workshop.

During the workshop the activities for the students include:

• Measuring the levels of glucose and diagnosing subjects as to whether they may or may not have diabetes.
• Chromatography to investigate glucose, insulin and free fatty acids
• Food evaluation for calorie content
• Quiz on diabetic complications

We also take part in the National Science and Engineering Week. Previously, we have created a stand to help teenagers demonstrate their understanding of what a balanced meal would be and we have tackled issues such as obesity and anorexia.