Reader in Developmental Endocrinology
British Heart Foundation Senior Fellow
Department of Clinical Biochemistry
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.
Blackmore HL, Piekarz AV, Fernandez-Twinn DS, Mercer JR, Figg N, Bennett M, Ozanne SE. (2012). Poor maternal nutrition programmes a pro-atherosclerotic phenotype in ApoE-/- mice. Clin Sci (Lond), 123(4):251-7. PMID: 22375564. PMCID: PMC3341090.
Ferland-McCollough D, Fernandez-Twinn DS, Cannell IG, David H, Warner M, Vaag AA, Bork-Jensen J, Brøns C, Gant TW, Willis AE, Siddle K, Bushell M, Ozanne SE. (2012). Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. Cell Death Differ, 19(6):1003-12. PMID: 22223106. PMCID: PMC3354052.
Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns W, Tadayyon M, O'Neil LP, Murrell A, Ling C, Constancia M, Ozanne SE. (2011). Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. PNAS, 108(13):5449-54. PMID: 21385945. PMCID: PMC3069181.
Cottrell EC, Martin-Gronert MS, Fernandez-Twinn DS, Luan J, Berends LM, Ozanne SE. (2011). Leptin-independent programming of adult body weight and adiposity in mice. Endocrinology, 152(2):476-82. PMID: 21209019.
Rooney K and Ozanne SE. 2011. Maternal over-nutrition and offspring obesity predisposition: targets for preventative interventions. Int. J Obes (Lond), 35(7):883-90. PMID: 21587200.
Chen JH, Tarry-Adkins JL, Matharu K, Yeo GS, Ozanne SE. (2010). Maternal protein restriction affects gene expression profiles in the kidney at weaning with implications for the regulation of renal function and lifespan. Clin Sci (Lond), 119(9):373-84. PMID: 20528770.
Tarry-Adkins JL, Chen JH, Jones RH, Smith NH, Ozanne SE. (2010). Poor maternal nutrition leads to alterations in oxidative stress, antioxidant defense capacity, and markers of fibrosis in rat islets: potential underlying mechanisms for development of the diabetic phenotype in later life. FASEB J, 24(8):2762-71. PMID: 20388698.
Fernandez Twinn DS, Ekizoglou S, Martin-Gronert MS, Tarry-Adkins J, Wayman AP, Warner MJ, Luan JA, Gusterson BA, Ozanne SE. (2010). Poor early growth and excessive adult calorie intake independently and additively affect mitogenic signalling and increase mammory tumor susceptibility. Carcinogenesis, 31(10):1873-81. PMID: 20460357.
Cripps RL, Martin-Gronert MS, Archer ZA, Hales CN, Mercer JG, Ozanne SE. (2009). Programming of hypothalamic energy balance gene expression in rats by maternal diet during pregnancy and lactation. Clin Sci (Lond), 117(2):85-89. PMID: 19152506.
Cottrell EC, Cripps RL, Duncan JS, Barrett P, Mercer JG, Herwig A, Ozanne SE. (2009). Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat. Am J Physiol Regul Integr Comp Physiol, 296(3):R631-9. PMID: 19144754. PMCID: PMC2665846.
Tarry-Adkins JL, Chen JH, Smith NS, Jones RH, Cherif H, Ozanne SE. (2009). Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets. FASEB J, 23(5):1521-8. PMID: 19126595.
Tarry-Adkins JL, Martin-Gronert MS, Chen JH, Cripps RL, Ozanne SE. (2008). Maternal diet influences DNA damage, aortic telomere length, oxidative stress, and antioxidant defense capacity in rats. FASEB J, 22(6):2037-44. PMID: 18230683.
Martin-Gronert MS, Tarry-Adkins JL, Cripps RL, Chen JH, Ozanne SE (2008). Maternal protein restriction leads to early life alterations in the expression of key molecules involved in the aging process in rat offspring. Am J Physiol Regul Integr Comp Physiol, 294(2):R494-500. PMID: 18094069.
Ozanne SE, Constância M. (2007). Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endocrinol Metab, 3(7):539-46. PMID: 17581623.
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):2993-9. PMID: 17063325.
Ozanne SE & Hales CN. (2004). Lifespan: Catch-up growth and obesity in male mice. Nature, 427(6973):411-2. PMID: 14749819.