Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A short-term transition from a high-fat diet to a normal-fat diet before pregnancy exacerbates female mouse offspring obesity

International Journal of Obesity volume 40, pages 564–572 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

Recent findings have highlighted the detrimental influence of maternal overnutrition and obesity on fetal development and early life development. However, there are no evidence-based guidelines regarding the optimal strategy for dietary intervention before pregnancy.

Subjects/Methods:

We used a murine model to study whether switching from a high-fat (HF) diet to a normal-fat (NF) diet (H1N group) 1 week before pregnancy could lead to in utero reprogramming of female offspring obesity; comparator groups were offspring given a consistent maternal HF group or NF group until weaning. After weaning, all female offspring were given the HF diet for either 9 or 12 weeks before being killed humanely.

Results:

H1N treatment did not result in maternal weight loss before pregnancy. NF offsprings were neither obese nor glucose intolerant during the entire experimental period. H1N offsprings were most obese after the 12-week postweaning HF diet and displayed glucose intolerance earlier than HF offsprings. Our mechanistic study showed reduced adipocyte insulin receptor substrate 1 (IRS1) and hepatic IRS2 expression and increased adipocyte p-Ser636/639 and p-Ser612 of H1N or HF offspring compared with that in the NF offspring. Among all groups, the H1N offspring had lowest level of IRS1 and the highest levels of p-Ser636/639 and p-Ser612 in gonadal adipocyte. In addition, the H1N offspring further reduced the expression of Glut4 and Glut2, vs those of the HF offspring, which was lower compared with the NF offspring. There were also enhanced expression of genes inhibiting glycogenesis and decreased hepatic glycogen in H1N vs HF or NF offspring. Furthermore, we showed extremely higher expression of lipogenesis and adipogenesis genes in gonadal adipocytes of H1N offspring compared with all other groups.

Conclusions:

Our results suggest that a transition from an HF diet to an NF diet shortly before pregnancy, without resulting in maternal weight loss, is not necessarily beneficial and may have deleterious effects on offspring.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Flegal KM, Carroll MD, Ogden CL, Curtin LR . Prevalence and trends in obesity among US adults, 1999–2008. JAMA 2010; 303: 235–241.

    CAS  PubMed  Google Scholar 

  2. Ogden CL, Carroll MD, Kit BK, Flegal KM . Prevalence of obesity in the United States, 2009–2010. NCHS Data Brief 2012; 82: 1–8.

    Google Scholar 

  3. Vahratian A . Prevalence of overweight and obesity among women of childbearing age: results from the 2002 National Survey of Family Growth. Matern Child Health J 2009; 13: 268–273.

    Article  PubMed  Google Scholar 

  4. Yang Z, Huffman SL . Nutrition in pregnancy and early childhood and associations with obesity in developing countries. Matern Child Nutr 2013; 9: 105–119.

    Article  PubMed  Google Scholar 

  5. Williams L, Seki Y, Vuguin PM, Charron MJ . Animal models of in utero exposure to a high fat diet: a review. Biochim Biophys Acta 2014; 1842: 507–519.

    Article  CAS  PubMed  Google Scholar 

  6. Simar D, Chen H, Lambert K, Mercier J, Morris MJ . Interaction between maternal obesity and post-natal over-nutrition on skeletal muscle metabolism. Nutr Metab Cardiovasc Dis 2012; 22: 269–276.

    Article  CAS  PubMed  Google Scholar 

  7. Rooney K, Ozanne SE . Maternal over-nutrition and offspring obesity predisposition: targets for preventative interventions. Int J Obes (Lond) 2011; 35: 883–890.

    Article  CAS  Google Scholar 

  8. Muhlhausler BS, Ong ZY . The fetal origins of obesity: early origins of altered food intake. Endocr Metab Immune Disord Drug Targets 2011; 11: 189–197.

    Article  CAS  PubMed  Google Scholar 

  9. Vickers MH . Developmental programming and adult obesity: the role of leptin. Curr Opin Endocrinol Diabetes Obes 2007; 14: 17–22.

    Article  CAS  PubMed  Google Scholar 

  10. Taylor PD, Poston L . Developmental programming of obesity in mammals. Exp Physiol 2007; 92: 287–298.

    Article  CAS  PubMed  Google Scholar 

  11. Barker DJ . The developmental origins of adult disease. J Am Coll Nutr 2004; 23: 588S–595S.

    Article  CAS  PubMed  Google Scholar 

  12. Barker DJ . Developmental origins of adult health and disease. J Epidemiol Commun Health 2004; 58: 114–115.

    Article  CAS  Google Scholar 

  13. Tenenbaum-Gavish K, Hod M . Impact of maternal obesity on fetal health. Fetal Diagn Ther 2013; 34: 1–7.

    Article  PubMed  Google Scholar 

  14. Leddy MA, Power ML, Schulkin J . The impact of maternal obesity on maternal and fetal health. Rev Obstet Gynecol 2008; 1: 170–178.

    PubMed  PubMed Central  Google Scholar 

  15. Whitaker RC, Wright JA, Pepe MS, Seidel KD, Dietz WH . Predicting obesity in young adulthood from childhood and parental obesity. N Engl J Med 1997; 337: 869–873.

    Article  CAS  PubMed  Google Scholar 

  16. van den Broek M, Leermakers ET, Jaddoe VW, Steegers EA, Rivadeneira F, Raat H et al. Maternal dietary patterns during pregnancy and body composition of the child at age 6 y: the Generation R Study. Am J Clin Nutr 2015; 102: 873–880.

    Article  CAS  PubMed  Google Scholar 

  17. Ainge H, Thompson C, Ozanne SE, Rooney KB . A systematic review on animal models of maternal high fat feeding and offspring glycaemic control. Int J Obes (Lond) 2011; 35: 325–335.

    Article  CAS  Google Scholar 

  18. Alfaradhi MZ, Ozanne SE . Developmental programming in response to maternal overnutrition. Front Genet 2011; 2: 27.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Masuyama H, Hiramatsu Y . Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression. Endocrinology 2012; 153: 2823–2830.

    Article  CAS  PubMed  Google Scholar 

  20. Ornellas F, Souza-Mello V, Mandarim-de-Lacerda CA, Aguila MB . Programming of obesity and comorbidities in the progeny: lessons from a model of diet-induced obese parents. PLoS One 2015; 10: e0124737.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Stettler N, Kumanyika SK, Katz SH, Zemel BS, Stallings VA . Rapid weight gain during infancy and obesity in young adulthood in a cohort of African Americans. Am J Clin Nutr 2003; 77: 1374–1378.

    Article  CAS  PubMed  Google Scholar 

  22. Ravelli GP, Stein ZA, Susser MW . Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976; 295: 349–353.

    Article  CAS  PubMed  Google Scholar 

  23. Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP . Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 1999; 70: 811–816.

    Article  CAS  PubMed  Google Scholar 

  24. Law CM, Barker DJ, Osmond C, Fall CH, Simmonds SJ . Early growth and abdominal fatness in adult life. J Epidemiol Commun Health 1992; 46: 184–186.

    Article  CAS  Google Scholar 

  25. Danielzik S, Czerwinski-Mast M, Langnase K, Dilba B, Muller MJ . Parental overweight, socioeconomic status and high birth weight are the major determinants of overweight and obesity in 5-7 y-old children: baseline data of the Kiel Obesity Prevention Study (KOPS). Int J Obes Relat Metab Disord 2004; 28: 1494–1502.

    Article  CAS  PubMed  Google Scholar 

  26. Procter SB, Campbell CG . Position of the Academy of Nutrition and Dietetics: nutrition and lifestyle for a healthy pregnancy outcome. J Acad Nutr Diet 2014; 114: 1099–1103.

    Article  PubMed  Google Scholar 

  27. Kaiser LL, Campbell CG . Practice paper of the Academy of Nutrition and Dietetics abstract: nutrition and lifestyle for a healthy pregnancy outcome. J Acad Nutr Diet 2014; 114: 1447.

    Article  PubMed  Google Scholar 

  28. Shapira N . Prenatal nutrition: a critical window of opportunity for mother and child. Womens Health (Lond Engl) 2008; 4: 639–656.

    Article  CAS  Google Scholar 

  29. Krasnow SM, Nguyen ML, Marks DL . Increased maternal fat consumption during pregnancy alters body composition in neonatal mice. Am J Physiol Endocrinol Metab 2011; 301: E1243–E1253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hwang LL, Wang CH, Li TL, Chang SD, Lin LC, Chen CP et al. Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obesity 2010; 18: 463–469.

    Article  CAS  PubMed  Google Scholar 

  31. Mischke M, Pruis MG, Boekschoten MV, Groen AK, Fitri AR, van de Heijning BJ et al. Maternal Western-style high fat diet induces sex-specific physiological and molecular changes in two-week-old mouse offspring. PLoS One 2013; 8: e78623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yan X, Huang Y, Zhao JX, Rogers CJ, Zhu MJ, Ford SP et al. Maternal obesity downregulates microRNA let-7 g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development. Int J Obes (Lond) 2013; 37: 568–575.

    Article  CAS  Google Scholar 

  33. Wu T, Deng S, Li WG, Yu Y, Li F, Mao M . Maternal obesity caused by overnutrition exposure leads to reversal learning deficits and striatal disturbance in rats. PLoS One 2013; 8: e78876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nicholas LM, Morrison JL, Rattanatray L, Ozanne SE, Kleemann DO, Walker SK et al. Differential effects of exposure to maternal obesity or maternal weight loss during the periconceptional period in the sheep on insulin signalling molecules in skeletal muscle of the offspring at 4 months of age. PLoS One 2013; 8: e84594.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Martin-Gronert MS, Fernandez-Twinn DS, Poston L, Ozanne SE . Altered hepatic insulin signalling in male offspring of obese mice. J Dev Origins Health Dis 2010; 1: 184–191.

    Article  CAS  Google Scholar 

  36. Kahraman S, Dirice E, De Jesus DF, Hu J, Kulkarni RN . Maternal insulin resistance and transient hyperglycemia impacts the metabolic and endocrine phenotypes of offspring. Am J Physiol Endocrinol Metab 2014; 307: E906–E918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Desai M, Jellyman JK, Han G, Beall M, Lane RH, Ross MG . Maternal obesity and high-fat diet program offspring metabolic syndrome. Am J Obstet Gynecol 2014; 211: 237 e231–237 e213.

    Article  Google Scholar 

  38. Boura-Halfon S, Zick Y . Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 2009; 296: E581–E591.

    Article  CAS  PubMed  Google Scholar 

  39. Valverde AM, Burks DJ, Fabregat I, Fisher TL, Carretero J, White MF et al. Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Diabetes 2003; 52: 2239–2248.

    Article  CAS  PubMed  Google Scholar 

  40. Rother KI, Imai Y, Caruso M, Beguinot F, Formisano P, Accili D . Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes. J Biol Chem 1998; 273: 17491–17497.

    Article  CAS  PubMed  Google Scholar 

  41. Dong X, Park S, Lin X, Copps K, Yi X, White MF . Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest 2006; 116: 101–114.

    Article  CAS  PubMed  Google Scholar 

  42. Wood IS, Trayhurn P . Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 2003; 89: 3–9.

    Article  CAS  PubMed  Google Scholar 

  43. Burcelin R, Dolci W, Thorens B . Glucose sensing by the hepatoportal sensor is GLUT2-dependent: in vivo analysis in GLUT2-null mice. Diabetes 2000; 49: 1643–1648.

    Article  CAS  PubMed  Google Scholar 

  44. Guillam MT, Burcelin R, Thorens B . Normal hepatic glucose production in the absence of GLUT2 reveals an alternative pathway for glucose release from hepatocytes. Proc Natl Acad Sci USA 1998; 95: 12317–12321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hosokawa M, Thorens B . Glucose release from GLUT2-null hepatocytes: characterization of a major and a minor pathway. Am J Physiol Endocrinol Metab 2002; 282: E794–E801.

    Article  CAS  PubMed  Google Scholar 

  46. Rkhzay-Jaf J, O'Dowd JF, Stocker CJ . Maternal obesity and the fetal origins of the metabolic syndrome. Curr Cardiovasc Risk Rep 2012; 6: 487–495.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Oken E, Gillman MW . Fetal origins of obesity. Obes Res 2003; 11: 496–506.

    Article  PubMed  Google Scholar 

  48. Willmer M, Berglind D, Sørensen TI, Näslund E, Tynelius P, Rasmussen F . Surgically induced interpregnancy weight loss and prevalence of overweight and obesity in offspring. PLoS One 2013; 8: e82247.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Dixon JB, Dixon ME, O'Brien PE . Birth outcomes in obese women after laparoscopic adjustable gastric banding. Obstet Gynecol 2005; 106: 965–972.

    Article  PubMed  Google Scholar 

  50. Bennett WL, Gilson MM, Jamshidi R, Burke AE, Segal JB, Steele KE et al. Impact of bariatric surgery on hypertensive disorders in pregnancy: retrospective analysis of insurance claims data. BMJ 2010; 340: c1662.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hezelgrave NL, Oteng-Ntim E . Pregnancy after bariatric surgery: a review. J Obes 2011; 2011: 501939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Karmon A, Sheiner E . Pregnancy after bariatric surgery: a comprehensive review. Arch Gynecol Obstet 2008; 277: 381–388.

    Article  PubMed  Google Scholar 

  53. Smith J, Cianflone K, Biron S, Hould FS, Lebel S, Marceau S et al. Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity. J Clin Endocrinol Metab 2009; 94: 4275–4283.

    Article  CAS  PubMed  Google Scholar 

  54. Kral JG, Biron S, Simard S, Hould FS, Lebel S, Marceau S et al. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Pediatrics 2006; 118: e1644–e1649.

    Article  PubMed  Google Scholar 

  55. Ehrlich SF, Hedderson MM, Feng J, Davenport ER, Gunderson EP, Ferrara et al. Change in body mass index between pregnancies and the risk of gestational diabetes in a second pregnancy. Obstet Gynecol 2011; 117: 1323–1330.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Villamor E, Cnattingius S . Interpregnancy weight change and risk of adverse pregnancy outcomes: a population-based study. Lancet 2006; 368: 1164–1170.

    Article  PubMed  Google Scholar 

  57. Bogaerts A, Van den Bergh BR, Ameye L, Witters I, Martens E, Timmerman D et al. Interpregnancy weight change and risk for adverse perinatal outcome. Obstet Gynecol 2013; 122: 999–1009.

    Article  PubMed  Google Scholar 

  58. KM Rasmussen, AL Yaktinen (eds). Weight Gain During Pregnancy: Reexamining the Guidelines. The National Academies Collection, National Institutes of Health: Bethesda, MD, USA, 2009.

  59. Gynecologists, ACoOa. ACOG Committee opinion no. 549: obesity in pregnancy. Obstet Gynecol 2013; 121: 5.

    Google Scholar 

  60. National Institute for Health and Care Excellence. Weight Management Before, During and after Pregnancy (PH27). National Institute for Health and Care Excellence: London, UK, 2010.

  61. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Management of Obesity in Pregnancy (C-Obs 49), 2013.

  62. Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M . Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One 2012; 7: e46057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431: 200–205.

    Article  CAS  PubMed  Google Scholar 

  64. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391: 900–904.

    Article  CAS  PubMed  Google Scholar 

  65. McCurdy CE, Bishop JM, Williams SM, Grayson BE, Smith MS, Friedman JE et al. Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Invest 2009; 119: 323–335.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Matsumoto M, Han S, Kitamura T, Accili D . Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 2006; 116: 2464–2472.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Brown MS, Goldstein JL . Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 2008; 7: 95–96.

    Article  CAS  PubMed  Google Scholar 

  68. Marcelino H, Veyrat-Durebex C, Summermatter S, Sarafian D, Miles-Chan J, Arsenijevic D et al. A role for adipose tissue de novo lipogenesis in glucose homeostasis during catch-up growth: a Randle cycle favoring fat storage. Diabetes 2013; 62: 362–372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sasaki A, Nakagawa I, Kajimoto M . Effect of protein nutrition throughout gestation and lactation on growth, morbidity and life span of rat progeny. J Nutr Sci Vitaminol 1982; 28: 543–555.

    Article  CAS  PubMed  Google Scholar 

  70. Hales CN, Barker DJ . Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595–601.

    Article  CAS  PubMed  Google Scholar 

  71. Hales CN, Barker DJ . The thrifty phenotype hypothesis. Br Med Bull 2001; 60: 5–20.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This project was supported by grants from the National Institutes of Health (NIH-1R15HL117238 to LX and National Center for Research Resources, 5P20RR016471-12/8 P20 GM103442-12 to LX and KZ) and the American Heart Association (Scientist Development Grant13SDG14650009 to LX).

Author information

Authors and Affiliations

  1. Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA

    Q Fu, P Olson, D Rasmussen, B Keith, M Williamson & L Xie

  2. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Q Fu

  3. Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA

    Q Fu & L Xie

  4. Department of Pathology, University of North Dakota, Grand Forks, ND, USA

    K K Zhang

Authors
  1. Q Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Keith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Williamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K K Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Xie.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, Q., Olson, P., Rasmussen, D. et al. A short-term transition from a high-fat diet to a normal-fat diet before pregnancy exacerbates female mouse offspring obesity. Int J Obes 40, 564–572 (2016). https://doi.org/10.1038/ijo.2015.236

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2015.236

This article is cited by

Search

Advanced search

Quick links