CoChat
Sign Up
Cited by 32Birth, Development, and HealthRegulation of Appetite and ObesityGestational Diabetes Research and Management

Elevated glucocorticoids during ovine pregnancy increase appetite and produce glucose dysregulation and adiposity in their granddaughters in response to ad libitum feeding at 1 year of age

Open access
Long, Nathan M., Smith, Derek T., Ford, Stephen P., Nathanielsz, Peter W.·2013·American Journal of Obstetrics and Gynecology
DOI 10.1016/j.ajog.2013.05.051PMC PMC3786012
Open this paper in CoChat — free account

Abstract

Objective Synthetic glucocorticoids (sGCs) are administered to women threatening preterm labor. We have shown multigenerational endocrine and metabolic effects of fetal sGC exposure. We hypothesized that sGC exposure would alter the second filial generation (F2) offspring neonatal leptin peak that controls development of appetitive behavior with metabolic consequences. Study design F0 nulliparous ewes were bred to a single ram. Beginning at day 103 of gestation (term 150 days), dexamethasone (DEX) ewes received 4 injections of 2 mg DEX intramuscularly, 12 hours apart. Control ewes received saline. Ewes lambed naturally. At 22 months of age, F1 offspring were mated to produce F2 offspring. At 10 months of age, F2 female offspring were placed on an ad libitum feeding challenge for 12 weeks. Results DEX F2 female offspring did not show a postnatal leptin peak and their plasma cortisol concentration was elevated in the first days of life. During the feeding challenge, DEX F2 offspring consumed 10% more feed and gained 20% more weight compared with control F2 offspring. At the end of the feeding challenge, DEX F2 offspring had greater adiposity compared with control F2 offspring. F2 sGC offspring showed impaired insulin secretion in response to an intravenous glucose tolerance test. Conclusion sGC administration to F0 mothers eliminates the neonatal leptin peak in F2 female offspring potentially by inhibition caused by elevated cortisol in the DEX F2 offspring. F2 offspring showed increased appetite, weight gain, and adiposity during an ad libitum feeding challenge accompanied by decreased insulin response to an intravenous glucose tolerance test.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.ajog.2013.05.051

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In animal studies, excess glucocorticoid exposure in utero consistently programmes the offspring for increased adiposity.

    “In animal studies, excess glucocorticoid exposure in utero was consistently shown to programme the offspring for increased adiposity (Table 6 and [119–123]).”

    From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [119]

    The Results report greater adiposity in female sheep granddaughters of dexamethasone-treated ewes after an ad libitum feeding challenge, but no difference in body-fat measurements before it (page not provided). This supports a conditional, multigenerational effect, not the broader claim that in-utero glucocorticoid exposure consistently increases adiposity in offspring across animal studies. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 55

  1. [1]Yura S Itoh H Sagawa N Role of premature leptin peak in obesity resulting from intrauterine undernutrition Cell Metabolism 2005 1 371 378 16054086
  2. [2]Rayner DV Dalgliesh GD Duncan JS Hardie LJ Hoggard N Trayhurn Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats Am J Physiol 1997 273 R446 450 9249584
  3. [3]Elias CF Lee C Kelly J Leptin activates hypothalamic CART neurons projecting to the spinal cord Neuron 1998 21 1375 1385 9883730
  4. [4]Elmquist JK Ahima RS Elias CF Flier JS Saper CB Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamicánuclei Proceedings of the National Academy of Sciences 1998 95 741 746 PMC18491 9435263
  5. [5]Proulx K Clavel S Nault G Richard D Walker CD High Neonatal Leptin Exposure Enhances Brain GR Expression and Feedback Efficacy on the Adrenocortical Axis of Developing Rats Endocrinol 2001 142 4607 4616 11606425
  6. [6]Delahaye F Breton C Risold PY Maternal perinatal undernutrition drastically reduces postnatal leptin peak and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups Endocrinol 2008 149 470 475 18006626
  7. [7]Kirk SL Samuelsson AM Argenton M Dhonye H Kalamatiano T Poston L Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring PLoS ONE 2009 4 e5870 19516909 PMC2690656
  8. [8]Soret B Lee HJ Finley E Lee SC Vernon RG Regulation of differentiation of sheep subcutaneous and abdominal preadipocytes in culture J Endocrinol 1999 161 517 524 10333554
  9. [9]Long NM Ford SP Nathanielsz PW Maternal obesity eliminates the neonatal lamb plasma leptin peak J Physiology 2011 589 1455 1462 PMC3082103 21262878
  10. [10]Liggins GC Preterm delivery of foetal lambs infused with glucocorticoids J Endocrinol 1969 45 515 523 5366112
  11. [11]Liggins GC Howie RN A controlled trail of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in preterm infants Pediatrics 1972 50 515 525 4561295
  12. [13]Aida K Wang XL Wang J Li C McDonald TJ Nathanielsz PW Effect of betamethasone administration to the pregnant baboon at 0. 75 gestation on placental eNOS distribution and activity Placenta 2004 25 780 787 15451192
  13. [14]Rodriguez JS Zürcher NR Keenan KE Prenatal betamethasone exposure has sex specific effects in reversal learning and attention in juvenile baboons Am J Obstet Gynecol 2011 204 545.e1 10 21411054 PMC3118269
  14. [15]Jobe AH Wada N Berry LM Ikegami M Ervin MG Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep Am J Obstet Gynecol 1998 178 880 885 9609554
  15. [16]Newnham JP Evans SF Godfrey M Huang W Ikegami M Jobe A Maternal, but not fetal, administration of corticosteroids restricts fetal growth J Matern Fetal Med 1997 8 81 87 10338060
  16. [17]Johnson JWC Mitzner W Beck JC Long-term effects of betamethasone on fetal development Am J Obstet Gynecol 1981 141 1053 1064 7315917
  17. [18]Banks BA Cnaan A Morgan MA Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group Am J Obstet Gynecol 1999 181 709 17 10486488
  18. [19]French NP Hagan R Evans SF Godfrey M Newnham JP Repeated antenatal corticosteroids: size at birth and subsequent development Am J Obstet Gynecol 1999 180 114 21 9914589
  19. [20]Bloom SL Sheffield JS McIntire DD Leveno KJ Antenatal dexamethasone and decreased birth weight Obstet Gynecol 2001 97 485 90 11275014
  20. [21]Long NM Shasa DR Ford SP Nathanielsz PW Growth and insulin dynamics in two generations of female offspring of mothers receiving a single course of synthetic glucocorticoids Am J Obstet Gynecol 2012 207 203.e1 8 22939726 PMC3919507
  21. [22]Long NM Ford SP Nathanielsz PW Multigenerational effects of fetal dexamethasone exposure on the hypothalamic-pituitary-adrenal axis of first and second generation female offspring Am J Obstet Gynecol 2013 208 217.e1 8 23220271 PMC3740770
  22. [23]Sloboda DM Newnham JP Challis JRG Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term J Endocrinol 2000 165 79 91 10750038
  23. [24]Sloboda DM Moss TJ Gurrin LC Newnham J Challis JRG The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function J Endocrinol 2002 172 71 81 11786375
  24. [25]Tang L Bi J Valego N Prenatal betamethasone exposure alters renal function in immature sheep: sex differences in effects Am J Physiol Regul Integr Comp Physiol 2010 299 R793 R803 20554936 PMC2944426
  25. [26]Drake AJ Walker BR Seckl JR Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats Am J Physiol Regul Integr Comp Physiol 2005 228 R34 R38 15178540
  26. [27]Nyirenda MJ Welberg LA Seck JR Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids-fetal effect or maternal influence? J Endocrinol 2001 170 653 60 11524246
  27. [28]Nijland MJ Mitsuya K Li C Epigenetic modification of fetal baboon hepatic phosphoenolpyruvate carboxykinase following exposure to moderately reduced nutrient availability J Physiol 2010 588 1349 359 20176628 PMC2872738
  28. [29]Zambrano E Martinez-Samayoa PM Bautista CJ Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation J Physiol 2005 566 225 236 15860532 PMC1464716
  29. [30]Langley-Evans SC Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis J Hypertens 1997 15 537 44 9170007
  30. [31]Langley-Evans SC McMullen S Developmental origins of adult disease Med Princ Pract 2010 19 87 98 20134170
  31. [32]McMullen S Langley-Evans SC Gambling L Lang C Swali A McArdle HJ A common cause for a common phenotype: the gatekeeper hypothesis in fetal programming Medical Hypotheses 2012 78 88 94 22047985 PMC3426771
  32. [33]National Research Council Nutrient Requirements of Sheep Washington, DC National Academy Press 1985
  33. [35]George LA Zhang L Tuersunjiang N Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function, in aged female offspring Am J Physiol Regul Integr Comp Physiol 2012 302 R795 R804 22277936 PMC3330774
  34. [36]Long NM George LA Uthlaut AB Maternal obesity and increased nutrient intake before and during gestation in the ewe results in altered growth, adiposity, and glucose tolerance in adult offspring J Anim Sci 2010 88 3546 3553 20622177
  35. [37]Ford SP Zhang L Zhu M Maternal obesity accelerates fetal pancreatic {beta}-cell but not {alpha}-cell development in sheep: prenatal consequences Am J Physiol Regul Integr Comp Physiol 2009 297 R835 R843 19605766 PMC2739779
  36. [38]Ford SP Hess BW Schwope MM Maternal undernutrition during early gestation in the ewe results in altered growth, adiposity, and glucose tolerance in male offspring J Anim Sci 2007 85 1285 1294 17224460
  37. [39]Zhu MJ Han B Tong J AMP-activated protein kinase signaling pathways are down regulated and skeletal muscle development impaired in fetuses of obese, over-nourished sheep J Physiol 2008 586 2651 2664 18372306 PMC2464338
  38. [40]Dong F Ford SP Nijland MJ Nathanielsz PW Ren J Influence of maternal undernutrition and overfeeding on cardiac ciliary neurotrophic factor receptor and ventricular size in fetal sheep J Nutr Biochem 2008 19 409 14 17869083 PMC2435388
  39. [41]Vonnahme KA Hess BW Hansen TR Maternal undernutrition from early- to mid-gestation leads to growth retardation, cardiac ventricular hypertrophy, and increased liver weight in the fetal sheep Biol Reprod 2003 69 133 140 12606329
  40. [43]Hill DJ Duvillie B Pancreatic development and adult diabetes Pediatr Res 2000 48 269 274 10960489
  41. [44]Hill DJ Petrik J Arany E Growth factors and the regulation of fetal growth Diabetes Care 1998 21 60B 69B 9704229
  42. [45]Petrik J Arany E McDonald TJ Hill DJ Apoptosis in the pancreatic islets cells of the neonatal rat is associated with a reduced expression in insulin-like growth factors II that may act as a survival factor Endocrinol 1998 139 2994 3004 9607811
  43. [46]Blondeau B Lesage J Czernichow P Dupouy JP Breant B Glucocorticoids impair fetal β-cell development in rats Am J Physiol Endocrinol Metab 2001 281 E592 E599 11500315
  44. [48]Han SI Yasuda K Kataoka K ATF2 interacts with Beta-cell-enriched transcription factors MafA Pdx1 and Beta2, and activated insulin gene transcription J Biol Chem 2011 286 10449 10456 21278380 PMC3060498
  45. [49]Mandrup-Poulsen T Beta-cell apoptosis: stimuli and signaling Diabetes 2001 50 Suppl 1 S58 63 11272204
  46. [50]Newsholme P Haber EP Hirabara SM Rebelato EL Procopio J Morgan D Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity J Physiol 2007 583 9 24 17584843 PMC2277225
  47. [52]Desai M Li T Ross MG Hypothalamic neurosphere progenitor cells in low birth-weight rat newborns: neurotropic effects of leptin and insulin Brain Research 2011 1378 29 42 21215735 PMC3472808
  48. [53]Gathercole LL Morgan SA Bujalska IJ Regulation of lipogenesis by glucocorticoids and insulin in human adipose tissue PLoS One 2011 6 e26223 22022575 PMC3194822
  49. [54]Masuzaki H Paterson J Shinyama H A transgenic model of visceral obesity and the metabolic syndrome Science 2001 294 2166 2170 11739957
  50. [55]Hou M Liu Y Zhu L Neonatal overfeeding induced by small litter rearing causes altered glucocorticoid metabolism in rats Plos One 2011 6 e25726 22073140 PMC3208550
  51. [56]Lukaszewski MA Mayeur S Fajardy I Maternal prenatal undernutrition programs adipose tissue gene expression in adult male rat offspring under high-fat diet Am J Physiol Endocrinol Metab 2011 301 E548 59 21712534
  52. [57]Whorwood CB Firth KM Budge H Symonds ME Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin ii receptor in neonatal sheep Endocrinol 2001 142 2854 2864 11416004
  53. [58]Guo C Li C Myatt L Nathanielsz PW Sun K Sexually dimorphic effects of maternal nutrient reduction on expression of genes regulating cortisol metabolism in fetal baboon adipose and liver tissues Diabetes 2013 62 1175 85 23238295 PMC3609578
  54. [59]Loehle M Schwab M Kadner S Dose-response effects of betamethasone on maturation of the fetal sheep lung Am J Obstet Gynecol 2010 202 186.e1 7 20022315 PMC2815247
  55. [60]Wapner RJ Sorokin Y Thom EA National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy Am J Obstet Gynecol 2006 195 633 642 16846587

Cited by

Sorted by citations

Authors
Long, N. M., Smith, D. T., Ford, S. P., & Nathanielsz, P. W.
Affiliations
University of Wyoming (US)
Corresponding author
Nathanielsz, Peter W.
ORCID
Venue
American Journal of Obstetrics and Gynecology
Publisher
Elsevier BV
Published
2013-10
Volume
209
Issue
4
Pages
353.e1-353.e9
ISSN
0002-9378 (ISSN-L)
DOI
10.1016/j.ajog.2013.05.051
PMC
PMC3786012
OpenAlex
W1986090235
Cited by
32
References
1
Citations by year
2026: 1 · 2025: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 1
FWCI
4.04
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Obstetrics and Gynecology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (2p20rr016474-09)
  • National Center for Research Resources (P20- RR-16474-04, P20-RR-016474)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-21350, P01HD021350)
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 › Gestational Diabetes Research and Management
Keywords
dexamethasone, transgenerational effects, fetal programming, appetite, adiposity, insulin secretion, glucose tolerance, cortisol, ewes, F2 progeny
MeSH terms
Animals, Appetite, Dexamethasone, Feeding Behavior, Female, Glucocorticoids, Glucose, Glucose Tolerance Test, Hydrocortisone, Pregnancy, Prenatal Exposure Delayed Effects, Sheep, Weight Gain, Glucose Intolerance, Leptin, Adiposity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review