Developmental programming

The incidence of obesity and related metabolic disorders (such as diabetes and cardiovascular diseases) is increasing at an alarming rate and represents a major public health issue for the 21st century.

Metabolic disease results from a complex interaction of genetic, physiologic, behavioural and environmental factors. Numerous hypotheses have been advanced to explain its current dramatic increase including increased food availability and reduced energy expenditure associated with changing work habits. The recent rate of increase suggests that environmental and behavioral influences, rather than genetic causes, are fuelling the present epidemic.

In this context, epidemiological and experimental evidence suggests that alterations in early life nutrition have a major impact on the health and wellbeing of offspring.

Our work focuses on the role of altered maternal nutrition (including undernutrition and high fat diets) on the growth and development of offspring. We are particularly interested in how nutrition affects obesity, the regulation of the metabolic hormones insulin and leptin, and reproductive function. We are also investigating possible intervention strategies (pharmacologic and nutritional) aimed at reversing this “programming” of adult disease. Our work spans in vitro methodology, molecular biology, immunohistochemistry and epigenetics through to whole animal physiology.

Dr Mark Vickers
Dr Deborah Sloboda

Associates within the Liggins Institute

Associate Professor Frank Bloomfield
Associate Professor Paul Hofman
Dr Jian Guan
Dr Mhoyra Fraser
Dr Joanna Perry
Dr Allan Sheppard
Professor Peter Gluckman
Professor David Cameron-Smith

Associates at The University of Auckland
Professor Peter Shepherd

Associates at other organisations

New Zealand
 
AgResearch: Tony Pleasants
Massey University: Professor David Raubenheimer, Professor Elwyn Firth, Professor Graeme Wake
University of Otago: Associate Professor Peter Dearden, Dr Mark Hampton

International

Australia
University of Western Australia: Professor Brendon Waddell, Dr Peter Mark, Assoc Prof Roger Hart, Professor John Newnham
University of Melbourne: Professor Martha Hickey
University of Newcastle: Dr Deborah Hodgson
Murdoch Children's Research Institute: Dr Richard Saffery

Canada
McGill University: Professor Michael Meaney
Michael Smith Foundation, British Columbia: Professor John Challis

Singapore
National University of Singapore: Assoc Prof Ravi Kambadur

United Kingdom
University of Cambridge: Professor Nabeel Affara
University of Southampton: Professor Mark Hanson

United States
University of Pennsylvania: Associate Professor Rebecca Simmons

• Transgenerational effects of nutrition transitions
• The impact of altered maternal nutrition on health and wellbeing of offspring
• Effect of maternal care on growth and development of offspring
• The role of leptin in reversing metabolic disorders induced by developmental programming
• The role of altered maternal nutrition on fetal and placental metabolism
• Maternal nutrition and reproductive fitness
• Effect of maternal exercise on body composition in offspring
• Epigenetics: role of altered maternal nutrition on DNA methylation profiles in offspring

Claudia Martinez (PhD)
Minglan Li (PhD)

• Effects of maternal nutrition on offspring ovarian function
• Intervention strategies to reverse adverse developmental programming 
• Central regulation of appetite control: impacts of early life nutrition
• Transgenerational effects of altered maternal nutrition: reproductive fitness

Developmental Programming: environmental factors, particularly maternal undernutrition, act in early life to programme the risks for adverse health outcomes, such as cardiovascular disease, obesity and the metabolic syndrome in offspring in adult life.

Metabolic Syndrome: the metabolic syndrome (also known as Syndrome X) is a cluster of abnormalities related to insulin resistance and associated with high risk for cardiovascular disease, obesity and diabetes.

Epigenetics: refers to changes in phenotype (appearance) or gene expression through non-genetic factors which cause an organism's genes to behave (or "express themselves") differently but do not involve changes in the DNA sequence of the genes.

Reproductive Strategies: life history theory links earlier ages of reproductive maturity to ecological circumstances such as the availability of energy and risks of predation. These concepts suggest that poor nutrition or a threatening environment in early life lead to accelerated maturation, through which the organism trades body size and longevity for earlier reproduction.

Physiological systems
We have established experimental models in small animals to investigate effects of altered maternal nutrition (eg, high fat nutrition, undernutrition, low protein diets) during critical windows of development such as pregnancy and lactation to examine disease risk in offspring. Our primary focus is on the links between diet and development of the metabolic syndrome and altered reproductive fitness.

We are also using the models to examine the effect of therapeutic interventions (nutritional or pharmacologic) in reversing the effects of a poor maternal diet.

In vitro techniques

• Cell culture in primary and established cell lines eg neuronal/adipocytes/hepatocytes
• cell counting and analysis via automated flow cytometry systems
• structural quantification (eg, neurite outgrowth, axonal sprouting) via Discovery 1 platform.

Biochemistry

• Radioimmunoassay (RIA)
• enzyme linked immuno-sorbent assay (ELISA)
• western blotting
• biochemistry via automated analytical systems
• mass spectrometry.

Histology

• Structural histology and immunohistochemistry (including immunofluorescence) in frozen and paraffin embedded tissues
• morphology quantification (eg, ovarian follicle counts) via Discovery 1 platform.

Molecular biology

• Gene expression via Illumina gene arrays and/or RT-PCR
• DNA methylation via Sequenom MassArray platform.

Body composition
Assessment of body composition using dual energy x-ray absorptiometry (DEXA) to quantify total and regional fat mass and bone density. This technique is non-invasive and allows precise serial measurements of subjects across the life course.

Behaviour
Standard behavioural tasks such as the Morris water maze, novel object recognition task and operant conditioning to examine memory and recall following nutritional interventions.

We also investigate the effect of altered maternal care on the development of offspring.

Hickey M, Doherty DA, Hart R, Norman R, Newnham JP, Mattes E, Atkinson H, Sloboda DM. Maternal and umbilical cord androgen concentrations do not predict digit ratio (2D:4D) in girls: a prospective cohort study (2010) (accepted) Psychoneurendocrinology.

Hart R, Sloboda DM, Doherty D, Norman R, Atkinson H, Dickinson J, Hickey M (2010) Circulating maternal testosterone concentrations at 18 weeks gestation predict circulating AMH in adolescence: a prospective cohort study Fertility and Sterility (accepted).

Hart R, Hickey M, Doherty D, Norman R, Atkinson H, Dickinson J, Sloboda DM (2010). Serum Anti-Mullerian Hormone (AMH) levels are elevated in adolescent girls with polycystic ovaries and the Polycystic Ovarian Syndrome (PCOS). Fertility and Sterility doi:10.1016/j.fertnstert.2009.11.002.

Guan J, Zhang R, Dale-Gandar L, Hodgkinson SC, Vickers MH. NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat Behavioural Brain Research (2010, in press)

Morris T, Vickers MH, Gluckman PD, Gilmour S, Affara N. Transcriptional profiling of rats subjected to gestational undernourishment: implications for the developmental origins of the metabolic syndrome. PLoS One 29;4(9):e7271.

Hart R, Sloboda DM, Doherty D, Norman R, Atkinson H, Newnham JP, Dickinson J, Hickey M (2009) Prenatal determinants of uterine volume and ovarian reserve in adolescence Journal of Clinical Endocrinology and Metabolism.Dec;94(12):4931-7. Epub 2009 Oct 21.

Torrens C, Hanson MA, Gluckman PD, Vickers MH. Maternal undernutrition leads to endothelial dysfunction in adult male rat offspring independent of postnatal diet. Br J Nutr 101(1):27-33, 2009

Sloboda DM, Howie G., Gluckman PD., Vickers M.H. (2009) Pre- and postnatal nutritional histories influence reproductive maturation and ovarian function in the rat. PLoS One. Aug 25;4(8):e6744.

Smith GC, Vickers MH, Cognard E, Shephard,PR. Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in rats: Implications for glucose metabolism and food choice behaviour. Schizophrenia Research 2009

Sloboda DM, Beedle A, Cupido C, Gluckman PD, Vickers MH. (2009) Impaired perinatal growth and longevity: a life history perspective. Current Gerentology and Geriatrics Research 2009:608740. Epub 2009 Sep 6

Vickers MH, Gilmour S, Gertler A, Breier BH, Tunny K, Waters MJ, Gluckman PD. The 20kDa placental hGH-V has diminished diabetogenic and lactogenic activities compared to 22kDa hGH-N whilst retaining anti-lipogenic activity. Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E629-37.

Hickey M, Sloboda DM, Atkinson, H, Doherty D, Franks S, Norman, R, Newnham, JP, Hart R. (2009) The relationship between maternal and umbilical cord androgen levels and Polycystic Ovarian Syndrome in adolescence: A prospective cohort study. Journal of Clinical Endocrinology and Metabolism Oct;94 (10):3714-20.

Howie G, Sloboda DM, Kamal T, Vickers MH. (2009) Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet. Journal of Physiology 587 (4): 905-915

Vickers MH, Guan J, Gustavsson M, Krägeloh CU, Breier BH, Davison M, Fong B, Norris C, McJarrow P, Hodgkinson SC. Supplementation with a complex mixture of bioactive lipids derived from milk to young rats results in improvements in parameters related to growth and cognition. Nutrition Research. 2009 Jun;29(6):426-35.

Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, Breier BH, Harris M. The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy. Endocrinology. 2008 Apr;149(4):1906-13.

Vickers MH. How does early life influence physical activity in childhood ? – evidence from animal studies. In. J. Pediatrics, 2009; 76 (SS3), 22-27

Gatford K.L., Owen J.A., Li S., Moss TJM, Newnham JP, Challis JRG, Sloboda DM. (2008) Repeated betamethasone treatment of pregnant sheep programs persistent reductions in circulating IGF-I and IGF-binding proteins in progeny. American Journal of Physiology, Endocrinology and Metabolism 295 (1) : E170-8.

Smith GC, Chaussade C, Vickers M, Jensen J, Shepherd PR Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat. Diabetologia. 2008 Dec;51(12):2309-17. Epub 2008 Oct 9

Pedrana G, Sloboda DM, Perez W., Newnham JP, Martin G.B. (2008) Effects of prenatal glucocorticoids on testicular development in sheep. Anatomia Histologia Embriologia 37(5):352-8.

Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, Beedle AS, Burdge GC, Hanson MA. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proceedings of the National Academy of Sciences; 104 (31), 12796-12800, 2007.

Vickers MH, Krechowec SO, Breier BH. Is later obesity programmed in utero? Current Drug Targets, 8, 1-28, 2007.

Vickers MH, Cupido C-L, Gluckman PD. Developmental programming of Obesity and Type 2 Diabetes. Fetal and Maternal Medicine Review, 18; 1-23, 2007.

Vickers MH. Developmental programming of adult obesity: the role of leptin. Current Opinion in Endocrinology, Diabetes and Obesity 14; 17-22, 2007.

Ikenasio-Thorpe BA, Breier BH, Vickers MH, Fraser M. Prenatal influences on susceptibility to diet-induced obesity are mediated by altered neuroendocrine gene expression. J Endocrinol. 193(1):31-7, 2007.

Gluckman, P.D.; Beedle, A.S.; Hanson, M.A.; Vickers, MH. Leptin Reversal of the Metabolic Phenotype: Evidence for the Role of Developmental Plasticity in the Development of the Metabolic Syndrome. Horm Res. 67(Suppl.1):115-120, 2007.

Vickers MH. Developmental programming and adult obesity: the role of leptin. Curr Opin Endocrinol Diabetes Obes. 14(1):17-22, 2007.

Braun T, Li S, Moss TJ, Newnham JP, Challis JR, Gluckman PD, Sloboda DM.
Maternal betamethasone administration reduces binucleate cell number and placental lactogen in sheep. J Endocrinol. 2007 Aug;194(2):337-47.

Sloboda DM, Hart R, Doherty DA, Pennell CE, Hickey M. Age at menarche: Influences of prenatal and postnatal growth. J Clin Endocrinol Metab. 2007 Jan;92(1):46-50.

Thompson NM, Norman AM, Donkin SS, Shankar RR, Vickers MH, Miles JL, Breier BH. Prenatal and postnatal pathways to obesity: different underlying mechanisms, different metabolic outcomes. Endocrinology. 148(5):2345-54 2007.

Landon J, Davison M, , Krägeloh C, Thompson NM, Miles JL, Vickers MH, Fraser M, Breier BH. Global undernutrition during gestation influences learning during adult life. Learning and Behavior 35;2: 79-86, 2007.

Sloboda DM, Moss TJ, Li S, Doherty D, Nitsos I, Challis JR, Newnham JP.Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E61-70.

• National Research Centre for Growth and Development (NRCGD)
• Health Research Council of New Zealand (HRC)
• Marsden Fund of the Royal Society
• Foundation for Research Science and Technology (FRST)
• Lottery Health
• Maurice and Phyllis Paykel Trust
• Auckland Medical Research Foundation (AMRF).

In addition we undertake commercial projects with partners including Fonterra and LactoPharma and we also hold joint grants with the University of Western Australia and the National University of Singapore.