MOD Research Projects

Current research projects within the Metabolism, Obesity, and Diabetes (MOD) research theme in CVS

The study of human monogenic lipodystrophy and insulin resistance is not only of relevance to those with these rare conditions, but also widens general understanding of adipose tissue physiology and insulin signalling.

Alström Syndrome is a rare autosomal recessive disease caused by biallelic mutations of the ALMS1 gene1. Cardiometabolic aspects of the syndrome cause major morbidity and mortality, and include obesity, insulin resistant diabetes, dyslipidaemia, cardiomyopathy, fatty liver and premature atherosclerosis. 

One of the rare diseases characterised by the Semple group is Mandibular Hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) disorder.

Insulin acts by binding to the transmembrane insulin receptor, triggering biochemical responses within target cells. Insulin resistance denotes reduced ability of insulin to lower blood glucose, and is associated with several major diseases. 

In the time shortly before and after birth (the first few months of life), the vital organs, including the heart and the lungs, undergo remarkable changes that are essential for the baby to survive once it is born. The changes that occur in the heart before birth set the foundations for later life, and influence the risk of developing heart disease in adulthood.

Women are becoming increasingly integrated into military training, and we don’t yet know how undertaking arduous roles physically affects women compared with men. We have recently identified significant health issues facing women in the military, but it isn’t known why. These issues include higher rates of physical injury (such as stress fracture) and psychological injury (such as post-traumatic stress disorder), compared with men in the military, and increased rates of referral to infertility services compared with civilian women of the same age.

We aim to study the relationship between changes in metabolic control and eye disease. This may inform screening strategies with respect to islet transplantation, therefore leading to improved medical outcomes. We will examine subjects before beginning insulin pump/islet transplantation at regular intervals for 1 year.

Demonstrating the function of Manganese in rat models

Using mouse models to study the development of Diabetes

Appropriate development and function of the placental vascular network is critical for maintaining fetal growth. In pregnant rats, early to mid-gestation exposure to dexamethasone, a potent synthetic glucocorticoid, reduces the complexity of placental vasculature, contributing to adverse fetal outcomes.

In collaboration with Prof Jim Wilson (Usher Institute) we exploit the “jack-pot effect” of human population isolates to empower genome wide association studies to identify new genes that regulate fat distribution; a major risk factor for type 2 diabetes and cardiovascular disease (CVD). We investigate the impact of the candidate genes on cellular function and whole animal physiology as part of a pre-clinical validation pipeline geared towards discovery of novel medicines for CVD.

Glucocorticoid excess, particularly in adipose tissue, drives increased cardiovascular disease risk, including visceral obesity, hyperglycemia, dyslipidemia, and hypertension. Thus, efforts to reduce glucocorticoid action in adipose tissue as a treatment for cardiometabolic disease have both scientific and clinical merit. Our research is focused on the delivery mechanism through which glucocorticoids are ‘targeted’ to metabolic tissues, with the aims of not only advancing our understanding of glucocorticoid action in cardiometabolic disease, but identifying novel pathways to limit adverse glucocorticoid exposure.

Some of our fat deposits, such as the omentum (the main abdominal fat) and the pericardium (around the heart) are rich in immune clusters containing IgM producing B cells important for early protection during infection. In addition, these immune clusters recruit large amounts of inflammatory cells during episodes of inflammation triggered by events such as peritonitis, pericarditis and myocardial infarction. Our lab aims to elucidate the function of these clusters and the mechanisms underlying their role in infection, inflammation and obesity.

A regulator of metabolic disease and beyond

5α-Reductases regulate metabolism of glucocorticoids and androgens. We have shown that inhibition of their activities either genetically or pharmacologically leads to increased risk of type 2 diabetes mellitus and are exploring the underlying mechanisms and degree of risk.

Brown adipose tissue functions to increase energy expenditure to generate heat. Researchers at the University of Edinburgh are investigating how best to activate this tissue in humans as a novel therapy for obesity and type 2 diabetes.

Obesity is associated with a number of adverse effects on health including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease (Figure 1B). In this recent started programme of work we are using techniques such as DNA immunoprecipitation and ion torrent sequencing (Figure 2) to study the role of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC) in obesity and its common sequelae.

Epidemiological studies have shown a link between exposure to an adverse environment in early life and an increased risk of cardiometabolic and neurodevelopmental disease. These ‘programmed’ effects are transmissible across generations through both male and female lines (Drake et al).

Obesity is a major risk factor for cardiovascular disease and numerous other pathologies. Given that obesity is defined by excessive adiposity, this health burden has motivated extensive research into the formation and function of white adipose tissue (WAT; Figure 1). Such research has revealed that WAT is a key regulator of metabolic health, both as a site for energy storage and as a major endocrine organ. More recently, there has been intense interest in brown adipose tissue (BAT), which might be a new target for treating obesity and related diseases (Figure 1). However, few people realise that adipocytes are also a major component of the bone marrow.

The pandemic of obesity threatens to reverse the downward secular trends in cardiovascular disease because of its associations with hyperglycaemia, dyslipidaemia and hypertension (the Metabolic Syndrome). Research in Edinburgh has focused on steroid hormones as mediators of the metabolic complications of obesity and the progression to cardiovascular disease (Ann Int Med 2004, PNAS 2005). Since the formation of the Centre for Cardiovascular Science (CVS) in 1997, this has become a major focus, with Wellcome Trust and BHF Programme Grants and infrastructural awards (BHF Int Physiol, WTCRF) facilitating translation from rodents to humans.

The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge.