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School of Clinical Medicine > Department of Clinical Biochemistry > Diabetes, Obesity & Insulin Action

Susan Ozanne
British Heart Foundation Lecturer

Contact Information

Phone 01223 762636
Fax 01223 330598
E-mail seo10@cam.ac.uk

Research Interests

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.

Selected Recent Publications

  1. Ozanne SE, Jensen CB, Tingey KJ, Martin-Gronert MS, Grunnet L, Brons C, Storgaad H & Vaag AA (2006) Decreased protein levels of key insulin signalling molecules in adipose tissue from young men with a low birthweight - potential link to increased risk of diabetes? Diabetologia 49(12):2993-2999. Abstract
  2. Chen JH & Ozanne SE (2006) Deep senescent human fibroblasts show diminished DNA damage foci but retain checkpoint capacity to oxidative stress. FEBS Let 580: 6669-6673. Abstract
  3. Martin-Gronert MS & Ozanne (2006) Maternal nutrition during pregnancy and health of the offspring. Biochem Soc Trans 34(Pt 5):779-82. Abstract
  4. Smith NH & Ozanne SE (2006) Are we what our mothers ate? maternal nutrition and disease. The Biochmist 28 (5): 5-7. Abstract
  5. Petry CJ, Jennings BJ, James LA, Hales CN & Ozanne SE (2006) Suckling a protein-restricted rat dam leads to diminished albuminuria in her male offspring in adult life: a longitudinal study. BMC Nepherol. 7 (1): 14. Abstract
  6. Fernandez-Twinn DS, Ekizoglou S, Gusterson BA, Luan J & Ozanne SE (2006) Compensatory mammary growth following protein restriction during pregnancy and lactation increases early-onset mammary tumor incidence in rats. Carcinogenesis. [Epub ahead of print] Abstract
  7. Fernandez-Twinn DS & Ozanne SE (2006) Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav  88(3): 234-243. Abstract
  8. Siddle K, Luzio JP & Ozanne SE (2006) Nick Hales: an appreciation of his life and work. Diabetologia.49(6): 1131-1133 No abstract available
  9. Smith NH & Ozanne SE (2006) Intrauterine origins of metabolic disease. Rev Gyn Per Pra 6: 211-217. Abstract
  10. Fernandez-Twinn DS, Ekizoglou S, Wayman A, Petry CJ & Ozanne SE (2006) Maternal low protein diet programs cardiac beta-adrenergic response and signalling in 3 month old male offspring. Am J Physiol 291(2):R429-436. Abstract
  11. Chen JH, Ozanne SE, & Hales CN (2005) Analysis of expression of growth factor receptors in replicatively and oxidatively senescent human fibroblasts. FEBS Let 579: 6388-6394 Abstract
  12. Martin-Gronert MS & Ozanne SE (2005) Programming of appetite and type 2 diabetes. Early Hum Dev. 81(12):981-988 Abstract
  13. Tarry-Adkins J, Ozanne SE, Norden A, Cherif H & Hales CN (2005) Lower anti-oxidant capacity and elevated p53 and p21 may be a link between gender disparity in renal telomere shortening, albuminuria and longevity. Am J Physiol 290: F509-F516 Abstract
  14. Chen JH, Ozanne SE, & Hales CN (2005) Heterogeneity in premature senescence by oxidative stress correlates with differential DNA damage during the cell cycle. DNA Repair 4: 1140-1148 Abstract
  15. Ozanne SE & Hales CN (2005) Poor fetal growth followed by rapid postnatal catch-up growth leads to premature death. Mech Ageing Dev. 126(8):852-854 Abstract
  16. Cripps RL, Martin-Gronert MS & Ozanne SE (2005) Fetal and perinatal programming of appetite. Clin Sci 109: 1-11 Abstract
  17. Gardner DS, Tingey K, Van Bon BW, Ozanne SE, Wilson V, Dandrea J, Keisler DH, Stephenson T, & Symonds ME (2005) Programming of glucose-insulin metabolism in adult sheep after maternal undernutrition. Am J Physiol Regul Integr Comp Physiol. 289(4):R947-954 Abstract
  18. Buckley AJ, Keseru B, Briody J, Thompson M, & Ozanne SE (2005) Altered body composition and metabolism in the male offspring of high fat-fed rats. Metabolism. 54(4):500-507. Abstract 
  19. Ozanne SE, Jensen CB, Tingey KJ, Storgaard H, Madsbad S & Vaag AA (2005) Low birth weight is associated with specific changes in muscle insulin signaling protein expression. Diabetologia 48: 547-552 Abstract
  20. Fernandez-Twinn DS, Wayman A, Ekizoglou S, Martin MS, Hales CN & Ozanne SE (2005) Maternal protein restriction leads to hyperinsulinaemia and reduced insulin signaling protein expression in 21 month-old female rat offspring. Am J Physiol 288: R368-372 Abstract 
  21. Ozanne SE & Hales CN (2005) Poor fetal growth followed by rapid postnatal catch-up growth leads to premature death. Mech Ageing Dev 126: 852-854 Abstract
  22. Chen JH, Stoeber K, Kingsbury S, Ozanne SE, Williams GH, & Hales CN (2004) Loss of proliferative capacity and induction of senescence in oxidatively stressed human fibroblasts. J Biol Chem 279: 49439-49446 Abstract
  23. Ozanne SE, Fernandez-Twinn DS & Hales CN (2005) Fetal growth and adult diseases. Semin Perinatol. 28(1):81-87. Abstract
  24. Ozanne SE & Hales CN (2004) Lifespan: Catch-up growth and obesity in male mice. Nature 427: 411-412 Abstract
  25. Ozanne SE, Lewis R, Jennings BJ & Hales CN (2004) Early programming of weight gain in mice prevents the induction of obesity by a highly palatable diet. Clin Sci 106: 141-145 Abstract

 

Ten selected publications

Full list of publications

Funding

British Heart Foundation

Medical Research Council

BBSRC

European Union Media Centre

NIH

The Susan G. Komen Breast Cancer Foundation

Group Members

Jane Adkins

Jian-Hua Chen

Lizzy Cottrell

Roselle Cripps

Delia Hawkes

Huw Jones

Malgosia Martin

Ana Piekarz

Noel Smith

Denise Fernandez-Twinn

Adrian Wayman

Updated on 16/1/07