Professor of Developmental Endocrinology
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.
1: Martin-Gronert MS, Stocker CJ, Wargent ET, Cripps RL, Garfield AS, Jovanovic Z, D'Agostino G, Yeo GS, Cawthorne MA, Arch JR, Heisler LK, Ozanne SE. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. Dis Model Mech. 2016 Jan 14. pii: dmm.023903. [Epub ahead of print] PubMed PMID: 26769798.
2: Tarry-Adkins JL, Fernandez-Twinn DS, Hargreaves IP, Neergheen V, Aiken CE, Martin-Gronert MS, McConnell JM, Ozanne SE. Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternalnutrition and accelerated postnatal growth. Am J Clin Nutr. 2015 Dec 30. pii: ajcn119834. [Epub ahead of print] PubMed PMID: 26718412.
3: Sandovici I, Hammerle CM, Cooper WN, Smith NH, Tarry-Adkins JL, Dunmore BJ, Bauer J, Andrews SR, Yeo GS, Ozanne SE, Constância M. Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets. Diabetologia. 2015 Dec 23. [Epub ahead of print] PubMed PMID: 26699651.
4: Aiken CE, Tarry-Adkins JL, Penfold NC, Dearden L, Ozanne SE. Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet. FASEB J. 2015 Dec 23. pii: fj.15-280800. [Epub ahead of print] PubMed PMID:26700734.
5: Aiken CE, Tarry-Adkins JL, Ozanne SE. Transgenerational Developmental Programming of Ovarian Reserve. Sci Rep. 2015 Nov 3;5:16175. doi: 10.1038/srep16175. PubMed PMID: 26525600; PubMed Central PMCID: PMC4630792.
6: Ong KK, Kennedy K, Castañeda-Gutiérrez E, Forsyth S, Godfrey KM, Koletzko B, Latulippe ME, Ozanne SE, Rueda R, Schoemaker MH, van der Beek EM, van Buuren S, Fewtrell M. Postnatal growth in preterm infants and later health outcomes: a systematic review. Acta Paediatr. 2015 Oct;104(10):974-86. doi: 10.1111/apa.13128. Review. PubMed PMID: 26179961.
7: Dearden L, Ozanne SE. Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis. Front Neuroendocrinol. 2015 Oct;39:3-16. doi: 10.1016/j.yfrne.2015.08.001. Epub 2015 Aug 19. Review. PubMed PMID: 26296796.
8: de Rooij SR, van Pelt AM, Ozanne SE, Korver CM, van Daalen SK, Painter RC, Schwab M, Viegas MH, Roseboom TJ. Prenatal undernutrition and leukocyte telomere length in late adulthood: the Dutch famine birth cohort study. Am J Clin Nutr. 2015 Sep;102(3):655-60. doi: 10.3945/ajcn.115.112326. Epub 2015 Jul 15. PubMed PMID: 26178721.
9: Fernandez-Twinn DS, Constância M, Ozanne SE. Intergenerational epigenetic inheritance in models of developmental programming of adult disease. Semin Cell Dev Biol. 2015 Jul;43:85-95. doi: 10.1016/j.semcdb.2015.06.006. Epub 2015 Jun 30.Review. PubMed PMID: 26135290.
10: Blackmore HL, Ozanne SE. Programming of cardiovascular disease across the life-course. J Mol Cell Cardiol. 2015 Jun;83:122-30. doi: 10.1016/j.yjmcc.2014.12.006. Epub 2014 Dec 12. Review. PubMed PMID: 25510678.
11: Ozanne SE. Epigenetic signatures of obesity. N Engl J Med. 2015 Mar 5;372(10):973-4. doi: 10.1056/NEJMcibr1414707. Review. PubMed PMID: 25738675.
12: Bork-Jensen J, Scheele C, Christophersen DV, Nilsson E, Friedrichsen M, Fernandez-Twinn DS, Grunnet LG, Litman T, Holmstrøm K, Vind B, Højlund K, Beck-Nielsen H, Wojtaszewski J, Ozanne SE, Pedersen BK, Poulsen P, Vaag A. Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes. Diabetologia. 2015 Feb;58(2):363-73. doi: 10.1007/s00125-014-3434-2. Epub 2014 Nov 19. PubMed PMID: 25403480; PubMed Central PMCID: PMC4287682.
13: Ozanne SE. Epigenetics and metabolism in 2014: Metabolic programming--knowns, unknowns and possibilities. Nat Rev Endocrinol. 2015 Feb;11(2):67-8. doi: 10.1038/nrendo.2014.218. Epub 2014 Dec 9. PubMed PMID: 25488478.
14: Bouret S, Levin BE, Ozanne SE. Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. Physiol Rev. 2015 Jan;95(1):47-82. doi: 10.1152/physrev.00007.2014. Review. PubMed PMID: 25540138; PubMed Central PMCID: PMC4281588.
15: Blackmore HL, Niu Y, Fernandez-Twinn DS, Tarry-Adkins JL, Giussani DA, Ozanne SE. Maternal diet-induced obesity programs cardiovascular dysfunction in adult male mouse offspring independent of current body weight. Endocrinology. 2014 Oct;155(10):3970-80. doi: 10.1210/en.2014-1383. Epub 2014 Jul 22. PubMed PMID:25051449; PubMed Central PMCID: PMC4255219.
16: Fernandez-Twinn DS, Alfaradhi MZ, Martin-Gronert MS, Duque-Guimaraes DE, Piekarz A, Ferland-McCollough D, Bushell M, Ozanne SE. Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms. Mol Metab. 2014 Jan 20;3(3):325-33. doi: 10.1016/j.molmet.2014.01.007. eCollection 2014 Jun. PubMed PMID: 24749062; PubMed Central PMCID: PMC3986586.
17: Berends LM, Fernandez-Twinn DS, Martin-Gronert MS, Cripps RL, Ozanne SE. Catch-up growth following intra-uterine growth-restriction programmes an insulin-resistant phenotype in adipose tissue. Int J Obes (Lond). 2013 Aug;37(8):1051-7. doi: 10.1038/ijo.2012.196. Epub 2012 Dec 11. PubMed PMID: 23229735; PubMed Central PMCID: PMC3734734.
18: Luyckx VA, Bertram JF, Brenner BM, Fall C, Hoy WE, Ozanne SE, Vikse BE. Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet. 2013 Jul 20;382(9888):273-83. doi: 10.1016/S0140 6736(13)60311-6. Epub 2013 May 31. Review. PubMed PMID: 23727166.
19: Tarry-Adkins JL, Blackmore HL, Martin-Gronert MS, Fernandez-Twinn DS, McConnell JM, Hargreaves IP, Giussani DA, Ozanne SE. Coenzyme Q10 prevents accelerated cardiac aging in a rat model of poor maternal nutrition and accelerated postnatal growth. Mol Metab. 2013 Sep 27;2(4):480-90. doi: 10.1016/j.molmet.2013.09.004. eCollection 2013. PubMed PMID: 24327963; PubMed Central PMCID: PMC3854989.
20: Fernandez-Twinn DS, Blackmore HL, Siggens L, Giussani DA, Cross CM, Foo R, Ozanne SE. The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation. Endocrinology. 2012 Dec;153(12):5961-71. doi: 10.1210/en.2012-1508. Epub 2012 Oct 15. PubMed PMID: 23070543; PubMed Central PMCID: PMC3568261.
21: Ivanova E, Chen JH, Segonds-Pichon A, Ozanne SE, Kelsey G. DNA methylation at differentially methylated regions of imprinted genes is resistant to developmental programming by maternal nutrition. Epigenetics. 2012 Oct;7(10):1200-10. doi: 10.4161/epi.22141. Epub 2012 Sep 11. PubMed PMID:22968513; PubMed Central PMCID: PMC3469461.
22: 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. Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. Cell Death Differ. 2012 Jun;19(6):1003-12. doi:10.1038/cdd.2011.183. Epub 2012 Jan 6. PubMed PMID: 22223106; PubMed Central PMCID: PMC3354052.
23: Ozanne SE. Sugaring appetite development: mechanisms of neuroendocrine programming. Endocrinology. 2011 Nov;152(11):4007-9. doi: 10.1210/en.2011-1659. PubMed PMID: 22021197.
24: Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns W, Tadayyon M, O'Neill LP, Murrell A, Ling C, Constância M, Ozanne SE. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5449-54. doi: 10.1073/pnas.1019007108. Epub 2011 Mar 8. PubMed PMID: 21385945; PubMed Central PMCID: PMC3069181.
25: Cottrell EC, Martin-Gronert MS, Fernandez-Twinn DS, Luan J, Berends LM, Ozanne SE. Leptin-independent programming of adult body weight and adiposity in mice. Endocrinology. 2011 Feb;152(2):476-82. doi: 10.1210/en.2010-0911. Epub 2011Jan 5. PubMed PMID: 21209019; PubMed Central PMCID: PMC3884597.
26: Alfaradhi MZ, Ozanne SE. Developmental programming in response to maternal overnutrition. Front Genet. 2011 Jun 3;2:27. doi: 10.3389/fgene.2011.00027. eCollection 2011. PubMed PMID: 22303323; PubMed Central PMCID: PMC3268582.
27: Samuelsson AM, Matthews PA, Argenton M, Christie MR, McConnell JM, Jansen EH, Piersma AH, Ozanne SE, Twinn DF, Remacle C, Rowlerson A, Poston L, Taylor PD. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension. 2008 Feb;51(2):383-92. Epub 2007 Dec 17. PubMed PMID: 18086952.
28: Jensen CB, Martin-Gronert MS, Storgaard H, Madsbad S, Vaag A, Ozanne SE. Altered PI3-kinase/Akt signalling in skeletal muscle of young men with low birth weight. PLoS One. 2008;3(11):e3738. doi: 10.1371/journal.pone.0003738. Epub 2008 Nov 17. PubMed PMID: 19011679; PubMed Central PMCID: PMC2580025.
29: Ozanne SE, Hales CN. Lifespan: catch-up growth and obesity in male mice. Nature. 2004 Jan 29;427(6973):411-2. PubMed PMID: 14749819.