Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition
Abstract
Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause. Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences that are induced by fetal programming. Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a behavioral trigger of adult disease. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (AD group) or at 30% of ad libitum intake, or undernutrition (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [a control diet or a hypercaloric (30% fat) diet]. Food intake in offspring from UN mothers was significantly elevated at an early postnatal age. It increased further with advancing age and was amplified by hypercaloric nutrition. UN offspring also showed elevated systolic blood pressure and markedly increased fasting plasma insulin and leptin concentrations. This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal programming and a key contributing factor in adult pathophysiology. We hypothesize that hyperinsulinism and hyperleptinemia play a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development.
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A mismatch between nutritional status in the womb and nutritional status once born can contribute to the development of obesity and metabolic disease.
“While potentially beneficial in times of famine, a mismatch between nutritional status in the womb and nutritional status once born can contribute to the development of obesity and metabolic disease [53,54].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [53]
Cites
Steinberg, H. O., Chaker, H., Leaming, R., Johnson, A., Brechtel, G., & Baron, A. D. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118709 · Cited by 1,687 · cited 1× · see citing works
“Thus secondary hyperinsulinism can have stimulating and undesirable effects, such as chronic renal sodium retention and increased sympathetic nervous system activity, whereas resistance in other tissues, such as the endothelium, can result in impaired vasodilation (3, 18).”
BackgroundObesity in Young Men after Famine Exposure in Utero and Early Infancy
Ravelli, G.-P., Stein, Z. A., & Susser, M. W. (1976) · New England Journal of Medicine · doi:10.1056/nejm197608122950701 · Cited by 1,647 · see citing works
The vasodilator action of insulin. Implications for the insulin hypothesis of hypertension.
Anderson, E. A., & Mark, A. L. (1993) · Hypertension · doi:10.1161/01.hyp.21.2.136 · Cited by 242 · see citing works
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Effect of In Utero and Early-Life Conditions on Adult Health and Disease
Gluckman, P. D., Hanson, M. A., Cooper, C., & Thornburg, K. L. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0708473 · Cited by 3,898 · see citing works
Self-citationDevelopmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming
Mcmillen, I. C., & Robinson, J. S. (2005) · Physiological Reviews · doi:10.1152/physrev.00053.2003 · Cited by 1,910 · see citing works
The Pathophysiology of Gestational Diabetes Mellitus
Plows, J. F., Stanley, J. L., Baker, P. N., Reynolds, C. M., & Vickers, M. H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113342 · Cited by 1,874 · see citing works
“While potentially beneficial in times of famine, a mismatch between nutritional status in the womb and nutritional status once born can contribute to the development of obesity and metabolic disease [53,54].”
BackgroundSelf-citationDevelopmental plasticity and human health
Bateson, P., Barker, D., Clutton-Brock, T., Deb, D., D'Udine, B., Foley, R. A., Gluckman, P., Godfrey, K., Kirkwood, T., Lahr, M. M., et al. (2004) · Nature · doi:10.1038/nature02725 · Cited by 1,742 · see citing works
Self-citationGlucose tolerance in adults after prenatal exposure to famine
Ravelli, A., van der Meulen, J., Michels, R., Osmond, C., Barker, D., Hales, C., & Bleker, O. (1998) · The Lancet · doi:10.1016/s0140-6736(97)07244-9 · Cited by 1,606 · see citing works
Ng, M., Gakidou, E., Lo, J., Abate, Y. H., Abbafati, C., Abbas, N., Abbasian, M., Abd ElHafeez, S., Abdel-Rahman, W. M., Abd-Elsalam, S., et al. (2025) · The Lancet · doi:10.1016/s0140-6736(25)00355-1 · Cited by 1,151 · see citing works
Gluckman, P. D., Hanson, M. A., & Beedle, A. S. (2007) · American Journal of Human Biology · doi:10.1002/ajhb.20590 · Cited by 1,006 · see citing works
Self-citationPredictive adaptive responses and human evolution
Gluckman, P. D., Hanson, M. A., & Spencer, H. G. (2005) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2005.08.001 · Cited by 713 · see citing works
Self-citationTen Putative Contributors to the Obesity Epidemic
McAllister, E. J., Dhurandhar, N. V., Keith, S. W., Aronne, L. J., Barger, J., Baskin, M., Benca, R. M., Biggio, J., Boggiano, M. M., Eisenmann, J. C., et al. (2009) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408390903372599 · Cited by 710 · see citing works
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Gluckman, P. D., Hanson, M. A., Buklijas, T., Low, F. M., & Beedle, A. S. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.102 · Cited by 627 · see citing works
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Gluckman, P. D., & Hanson, M. A. (2004) · Pediatric Research · doi:10.1203/01.pdr.0000135998.08025.fb · Cited by 607 · see citing works
Self-citationThe biology of developmental plasticity and the predictive adaptive response hypothesis
Bateson, P., Gluckman, P., & Hanson, M. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.271460 · Cited by 533 · see citing works
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Crispi, F., Miranda, J., & Gratacós, E. (2018) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2017.12.012 · Cited by 362 · see citing works
Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease
Burdge, G. C., & Lillycrop, K. A. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104751 · Cited by 372 · see citing works
Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective
Gluckman, P. D., & Hanson, M. A. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.240 · Cited by 333 · see citing works
Self-citationThe fetal, neonatal, and infant environments-the long-term consequences for disease risk
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Warner, M. J., & Ozanne, S. E. (2010) · Biochemical Journal · doi:10.1042/bj20091861 · Cited by 316 · see citing works
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Sferruzzi-Perri, A. N., & Camm, E. J. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00033 · Cited by 223 · see citing works
Maternal high fat diet consumption during the perinatal period programs offspring behavior
Sullivan, E. L., Nousen, E. K., & Chamlou, K. A. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2012.07.014 · Cited by 217 · see citing works
Minireview: Leptin and Development of Hypothalamic Feeding Circuits
Bouret, S. G., & Simerly, R. B. (2004) · Endocrinology · doi:10.1210/en.2004-0231 · Cited by 210 · see citing works
Bellinger, L., Sculley, D. V., & Langley-Evans, S. C. (2006) · International Journal of Obesity · doi:10.1038/sj.ijo.0803205 · Cited by 183 · see citing works
Bouret, S., Levin, B. E., & Ozanne, S. E. (2015) · Physiological Reviews · doi:10.1152/physrev.00007.2014 · Cited by 157 · see citing works
Ladyman, S. R., & Grattan, D. R. (2004) · Endocrinology · doi:10.1210/en.2004-0338 · Cited by 144 · see citing works
Baars, A., Oosting, A., Knol, J., Garssen, J., & Van Bergenhenegouwen, J. (2015) · Microorganisms · doi:10.3390/microorganisms3040641 · Cited by 135 · see citing works
Epigenetic programming, early life nutrition and the risk of metabolic disease
Block, T., & El-Osta, A. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.09.003 · Cited by 130 · see citing works
Life-long echoes–a critical analysis of the developmental origins of adult disease model
Gluckman, P. D., Hanson, M. A., Morton, S. M. B., & Pinal, C. S. (2005) · Neonatology · doi:10.1159/000082311 · Cited by 126 · see citing works
Self-citationReproduction in females: The role of the early life environment
Sloboda, D. M., Hickey, M., & Hart, R. (2011) · Human Reproduction Update · doi:10.1093/humupd/dmq048 · Cited by 94 · see citing works
Salomäki, H., Vähätalo, L. H., Laurila, K., Jäppinen, N. T., Penttinen, A.-M., Ailanen, L., Ilyasizadeh, J., Pesonen, U., & Koulu, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056594 · Cited by 92 · see citing works
Impact of maternal nutrition and metabolism on health of the offspring
Kunz, L. H., & King, J. C. (2007) · Seminars in Fetal and Neonatal Medicine · doi:10.1016/j.siny.2006.10.010 · Cited by 58 · see citing works
Fetal Growth Restriction and Postnatal Development
ELEFTHERIADES, M., CREATSAS, G., & NICOLAIDES, K. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1365.047 · Cited by 60 · see citing works
da Silva Aragão, R., Guzmán-Quevedo, O., Pérez-García, G., Manhães-de-Castro, R., & Bolaños-Jiménez, F. (2014) · British Journal Of Nutrition · doi:10.1017/s0007114514000865 · Cited by 35 · see citing works
van Deutekom, A. W., Chinapaw, M. J. M., Jansma, E. P., Vrijkotte, T. G. M., & Gemke, R. J. B. J. (2017) · PLOS ONE · doi:10.1371/journal.pone.0168186 · Cited by 19 · see citing works
Zulkafli, I. S., Waddell, B. J., & Mark, P. J. (2013) · Endocrinology · doi:10.1210/en.2013-1153 · Cited by 22 · see citing works
Mark, P. J., Wyrwoll, C. S., Zulkafli, I. S., Mori, T. A., & Waddell, B. J. (2014) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-12-39 · Cited by 19 · see citing works
Long-Term Effects of Placental Growth on Overweight and Body Composition
Eriksson, J. G., Gelow, J., Thornburg, K. L., Osmond, C., Laakso, M., Uusitupa, M., Lindi, V., Kajantie, E., & Barker, D. J. P. (2012) · International Journal of Pediatrics · doi:10.1155/2012/324185 · Cited by 14 · see citing works
Early life programming of energy balance
Cripps, R. L., Archer, Z. A., Mercer, J. G., & Ozanne, S. E. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351203 · Cited by 9 · see citing works
- Authors
- Vickers, M. H., Breier, B. H., Cutfield, W. S., Hofman, P. L., & Gluckman, P. D.
- Affiliations
- University of Auckland (NZ)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2000-07-01
- Volume
- 279
- Issue
- 1
- Pages
- E83-E87
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2135550286
- Cited by
- 999
- References
- 3
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 21 · 2022: 21 · 2021: 14 · 2020: 40 · 2019: 31 · 2018: 38 · 2017: 33 · 2016: 48 · 2015: 48 · 2014: 51 · 2013: 75 · 2012: 57
- FWCI
- 17.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- fetal programming, hyperphagia, obesity, hypertension, fetal malnutrition, hypercaloric diet, hyperinsulinism, hyperleptinemia, appetite, insulin action, fetal growth restriction, Wistar rats
- MeSH terms
- Animals, Animal Nutritional Physiological Phenomena, Animals, Newborn, Birth Weight, Blood Pressure, Energy Intake, Eating, Fasting, Female, Fetus, Hyperphagia, Hypertension, Insulin, Nutrition Disorders, Obesity, Pregnancy, Pregnancy Complications, Rats, Wistar, Leptin, Rats
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