Dr Susan Ozanne

Principal Research Associate
British Heart Foundation Senior Fellow
Department of Clinical Biochemistry
University of Cambridge Metabolic Research Laboratories

Email: seo10@hgm2010.org
Webpage link:

Early Programming of Appetite, Type 2 Diabetes, Breast Cancer and Ageing
The major focus of our research is to understand the mechanistic basis of the relationships between poor early growth and subsequent increased risk of type 2 diabetes, obesity, breast cancer and premature death. There are a large number of epidemiological studies suggesting that such relationships exist, however the molecular mechanisms mediating such phenomena are not understood.


Poor Early Growth and Diabetes

We carry out global and candidate expression studies at both the protein and RNA level using both rodent models and human tissues. Our aim is to identify the mechanisms by which poor early growth is linked to increased risk of type 2 diabetes and insulin resistance. In particular we are investigating the role played by the early environment.

Human studies: Tissue samples from low birth weight and control humans are used to establish insulin-signaling defects that may provide early indications of metabolic disease. Our insulin signaling protein expression studies in muscle and adipose tissue have already shown early defects in adult subjects who had a low birth weight. Ongoing studies in placenta will relate the expression of insulin signaling molecules to the nutritional status of both mother and baby.

Animal models: We are studying a rodent model of early nutritional growth restriction to identify molecular markers for prediction of risk of type 2 diabetes in later life. Nutritionally early growth restricted rats have been shown to develop impaired glucose tolerance in old age. At the molecular level, studies have shown defects in the pancreas, muscle, liver and adipose tissue of growth restricted rats. We are now extending these studies to determine the molecular mechanisms underlying these changes such as the role of epigenetic alterations.

Programming of Appetite

We have shown that appetite can be programmed by maternal nutrition during lactation and that the down regulation of appetite secondary to poor maternal nutrition is so powerful that it prevents diet-induced obesity in mice. We are currently involved in establishing the mechanisms underlying the early programming.

Animal Models: To determine the basis of appetite programming we have set up a model for poor fetal nutrition and then catch up growth in rats and mice using cross fostering techniques and altered maternal diet. In these animals, samples are taken at various time points and the expression of molecules, such as leptin and other adipocytokines, known to be involved with appetite regulation is examined. We are also determining the effect of the model on the neurodevelopment of appetite circuits using in situ hybridisation and tracing techniques.

Poor Early Growth and Breast Cancer

Epidemiological studies suggest that both low and high extremes of birthweight are associated with increased breast cancer risk. Some of the factors thought to mediate this risk are obesity and type-2 diabetes. It is also thought that an increased estrogen exposure mediates this risk in the high birth weight group. In animal studies, excessive in-utero estrogens have been shown to induce a higher mammary tumour risk and incidence. Our low-protein model is characterised by age-dependent loss of glucose tolerance, insulin resistance and type-2 diabetes. We have recently shown that maternal plasma estradiol levels are also 35% higher than controls in the last week of gestation. In the offspring, we have observed a period of retarded mammary development followed by rapid catch-up growth mainly of undifferentiated stem cells i.e structures such as terminal end buds and luminal epithelial cells. We are therefore investigating the hypothesis that fetal growth restriction followed by rapid catch-up growth increase an offspring's susceptibility to breast cancer in later life.

Oxidative Stress, Senescence and Ageing
For the past decade we have studied the long-term consequences of poor early growth using our rodent models and one of our most striking observations has been that life span can be increased or decreased by restricting their growth either during suckling or during fetal life respectively. These differences in lifespan are associated with differences in kidney telomere length. We have hypothesized that the rate of early growth may affect degrees of oxidative damage which in turn affect organ function leading to altered longevity. To test this we first investigated the effects of oxidative stress on regulation of stress response proteins,
DNA replication and induction of cellular senescence using human fibroblasts. In parallel with the in vitro cell system we are actively examining the telomere length and expression of stress response proteins such as p53, p21 and DNA damage checkpoint proteins such as gama-H2AX and 53BP1 as well as senescence marker, SA-beta-gal in organs of our model animals in order to understand the molecular mechanisms underlying the ageing process.

  

 

 
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