Early Programming of Obesity, Type 2 Diabetes and Ageing
The major focus of our research is to understand the mechanistic basis of the relationships between sub-optimal early life nutrition and subsequent increased risk of type 2 diabetes, obesity, and premature death. There are a large number of epidemiological studies suggesting that such relationships exist- for example from children exposed to maternal obesity or under-nutrition- however the molecular mechanisms mediating such phenomena are not understood. Our goal is to define these mechanisms and to use this understanding to develop rational intervention strategies.
Cardiovascular health: We have shown that the offspring of obese mothers develop cardiac hypertrophy, and this is associated with impaired cardiac function. These impairments in cardiac function could lead to increased risk of heart disease in later life. This phenotype is associated with alterations in cardiac microRNAs and a molecular switch in substrate utilization in fetuses that are exposed to an obese in utero environment. Recently, our studies have extended to incorporate echocardiographic imaging of cardiac function, which allows us to carry out non-invasive longitudinal assessments of cardiac function in parallel with blood pressure measurement in the offspring of obese mothers.
We have recently developed models of both phamocological (administration of metformin) and lifestyle (peri-gestational exercise) interventions during obese pregnancy. These intervention studies have provided vital clues as to the mechanism underlying the programming of offspring cardio-metabolic disorders in maternal obesity and we have shown rescue of some of the detrimental phenotypes in the offspring.
miRNAs as mediators of early life nutrition: We have a strong interest in defining the role of miRNAs as potential mediators of the effects of early life nutrition on gene expression and organ function. We use a range of molecular techniques to determine whether microRNAs in tissues such as the pancreas, liver and adipose tissue may be epigenetic regulators that are sensitive to programming by the nutritional environment associated and thus contribute to the dysfunction observed in these tissues. We have recently identified a subset of hepatic mircoRNAs sensitive to programming by maternal obesity, and used in vitro techniques to show a role for one of these microRNAs in development of early hepatic steatosis.
Control of food intake: We have shown that increased weight gain observed in offspring exposed to maternal obesity is associated with hyperphagia, implicating altered central regulation of food intake as an underlying cause. Our research shows that exposure to maternal obesity results in disruption of early hypothalamic development, and altered anatomy and the expression of key feeding pathways in adulthood. We are using a combination of molecular and physiological techniques to define the metabolic parameters that mediate the effects of maternal obesity on hypothalamic development, and establish whether this disrupted development underlies the hyperphagia- and ultimately obesity- we observe in the offspring of obese mothers.
Oxidative Stress, Senescence and Ageing: One of our most striking observations in offspring exposed to sub-optimal early life nutrition has been that life span can be increased or decreased by restricting growth either during suckling or fetal life, respectively. These differences in lifespan are associated with differences in telomere length in a number of organs. We are investigating whether the rate of early growth may affect degrees of oxidative damage, which in turn affect organ function leading to altered longevity.
Hufnagel A, Fernandez-Twinn DS, Blackmore HL, Ashmore TJ, Heaton RA, Jenkins B, Koulman A, Hargreaves IP, Aiken CE, Ozanne SE. Maternal but not fetoplacental health can be improved by metformin in a murine diet-induced model of maternal obesity and glucose intolerance. J Physiol. 2021 Sep 10. doi: 10.1113/JP281902. Online ahead of print. PMID: 34505282.
Ruth KS,….Ozanne SE…Perry JRB. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021 Aug;596(7872):393-397. doi: 10.1038/s41586-021-03779-7. Epub 2021 Aug 4. PMID: 34349265. PMCID: PMC7611832
de Almeida-Faria J, Duque-Guimarães DE, Ong TP, Pantaleão LC, Carpenter AA, Loche E, Kusinski LC, Ashmore TJ, Antrobus R, Bushell M, Fernandez-Twinn DS, Ozanne SE. Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark. Diabetologia. 2021 Apr;64(4):890-902. doi: 10.1007/s00125-020-05357-4. Epub 2021 Jan 27. PMID: 33501603 PMCID: PMC7940301
Dearden L, Buller S, Furigo IC, Fernandez-Twinn DS, Ozanne SE. Maternal obesity causes fetal hypothalamic insulin resistance and disrupts development of hypothalamic feeding pathways. Mol Metab. 2020 Sep 9;42:101079. doi: 10.1016/j.molmet.2020.101079. PMID: 32919096. PMCID: PMC7549144
Tarry-Adkins JL, Aiken CE, Ozanne SE. Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: a systematic review and meta-analysis. PLoS Medicine 2020 May 22; 17(5): e1003126.doi: 10.1371/journal.pmed.1003126. PMID: 32442232. PMCID: PMC7244100
Nicholas LM, Nagao M, Kusinski LC, Fernandez-Twinn DS, Eliasson L, Ozanne SE. (2019) Exposure to maternal obesity programs sex differences in pancreatic islets of the offspring in mice. Diabetologia. Nov 26. doi: 10.1007/s00125-019-05037-y PMID: 31773193. PMCID: PMC6946752
Tarry-Adkins JL, Aiken CE, Ozanne SE (2019) Neonatal, infant and childhood growth following metformin versus insulin treatment for gestational diabetes: a systematic review and meta-analysis PLoS Med. Aug 6;16(8):e1002848. doi: 10.1371/journal.pmed.1002848. PMID: 31386659. PMCID: PMC6684046
Beeson JH, Blackmore HL, Carr SK, Dearden L, Duque-Guimarães DE, Kusinski LC, Pantaleão LC, Pinnock AG, Aiken CE, Giussani DA, Fernandez-Twinn DS, Ozanne SE. (2018) Maternal Exercise intervention in obese pregnancy improves the cardiovascular health of the adult male offspring. Mol Metab. Oct;16:35-44. doi: 10.1016/j.molmet.2018.06.009. PMID: 30293577. PMCID: PMC6157615
Berends LM, Dearden L, Tung YCL, Voshol P, Fernanez-Twinn DS, Ozanne SE. (2018). Programming of central and peripheral insulin resistance by low birthweight and postnatal catch-up growth in male mice. Diabetologia. 2018 Oct;61(10):2225-2234. doi: 10.1007/s00125-018-4694-z. Epub 2018 Jul 24. PMID: 30043179. PMCID: PMC6133152
Loche E, Blackmore HL, Carpenter AA, Beeson JH, Pinnock A, Ashmore TJ, Aiken CE, de Almeida-Faria J, Schoonejans JM, Giussani DA, Fernandez-Twinn DS, Ozanne SE. Maternal diet-induced obesity programmes cardiac dysfunction in male mice independently of post-weaning diet. Cardiovasc Res. 2018 Aug 1;114(10):1372-1384. doi: 10.1093/cvr/cvy082. PMID: 29635288. PMCID: PMC6054211
Fernandez-Twinn DS, Gascoin G, Musial B, Carr S, Duque-Guimaraes D, Blackmore HL, Alfaradhi MZ, Loche E, Sferuzzi-Perri AN, Fowden AL, Ozanne SE. (2017). Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity. Sci Rep 2017 Mar 14;7:44650. doi: 10.1038/srep44650. PMID:28291256. PMCID: PMC5349590
Holland ML, Lowe R, Caton PW, Gemma C, Carbajosa G, Danson AF, Carpenter AA, Loche E, Ozanne SE & Rakyan VK (2016) Early life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice. Science 353:495-8. PMID: 27386920. PMCID: PMC5734613
Tarry-Adkins JL, Fernandez-Twinn DS, Hargreaves IP, Neergheen V, Aiken CE, Martin-Gronnert MS, McConnell JM & Ozanne SE (2016) Coenzyme Q10 prevents hepatic fibrosis, inflammation and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth. Am. J. Clin. Nutr. 103: 579-88. PMID: 26718412. PMCID: PMC4733260
Fernandez-Twinn DS, Alfaradhi MZ, Martin-Gronert MS, Duque-Guimaraes DE, Piekarz A, Ferland-McCollough D, Bushell M, Ozanne SE. (2014). 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. PMID: 24749062. PMCID: PMC3986586
Ferland-McCollough D, Fernandez-Twinn DS, Cannell IG, David H, Warner M, Vaag AA, Bork-Jensen J, Brons 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. 2012 Jun;19(6):1003-12. doi: 10.1038/cdd.2011.183. Epub 2012 Jan 6. 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 Hnf41 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. PMID: 21385945. PMCID: PMC3069181
Ozanne SE & Hales C.N (2004) Lifespan: catch-up growth and obesity in male mice. Nature: 427: 411-412. PMID: 14749819