Basic Science Article | Published:

Dlk1 expression relates to visceral fat expansion and insulin resistance in male and female rats with postnatal catch-up growth

Abstract

Background

Although prenatal and postnatal programming of metabolic diseases in adulthood is well established, the mechanisms underpinning metabolic programming are not. Dlk1, a key regulator of fetal development, inhibits adipocyte differentiation and restricts fetal growth.

Methods

Assess DLk1 expression in a Wistar rat model of catch-up growth following intrauterine restriction. Dams fed ad libitum delivered control pups (C) and dams on a 50% calorie-restricted diet delivered pups with low birth weight (R). Restricted offspring fed a standard rat chow showed catch-up growth (R/C) but those kept on a calorie-restricted diet did not (R/R).

Results

Decreased Dlk1 expression was observed in adipose tissue and skeletal muscle of R/C pups along with excessive visceral fat accumulation, decreased circulating adiponectin, increased triglycerides and HOMA-IR (from p < 0.05 to p < 0.0001). Moreover, in R/C pups the reduced Dlk1 expression in adipose tissue and skeletal muscle correlated with visceral fat (r = −0.820, p < 00001) and HOMA-IR (r = −0.745, p = 0.002).

Conclusions

Decreased Dlk1 expression relates to visceral fat expansion and insulin resistance in a rat model of catch-up growth following prenatal growth restriction. Modulation of Dlk1 expression could be among the targets for the early prevention of fetal programming of adult metabolic disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Barker, D. J., Osmond, C., Golding, J., Kuh, D. & Wadsworth, M. E. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 298, 564–567 (1989).

  2. 2.

    Ravelli, A. C. et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351, 173–177 (1998).

  3. 3.

    Bol, V. V., Delattre, A.-I., Reusens, B., Raes, M. & Remacle, C. Forced catch-up growth after fetal protein restriction alters the adipose tissue gene expression program leading to obesity in adult mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R291–R299 (2009).

  4. 4.

    Hales, C. N. & Ozanne, S. E. The dangerous road of catch-up growth. J. Physiol. 547(Pt 1), 5–10 (2003).

  5. 5.

    Barker, D. J. et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36, 62–67 (1993).

  6. 6.

    Sul, H. S. Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate. Mol. Endocrinol. 23, 1717–1725 (2009).

  7. 7.

    Mortensen, S. B. et al. Membrane-tethered delta-like 1 homolog (DLK1) restricts adipose tissue size by inhibiting preadipocyte proliferation. Diabetes 61, 2814–2822 (2012).

  8. 8.

    Falix, F. A., Aronson, D. C., Lamers, W. H. & Gaemers, I. C. Possible roles of DLK1 in the Notch pathway during development and disease. Biochim Biophys. Acta 1822, 988–995 (2012).

  9. 9.

    Prats-Puig, A. et al. The placental imprinted DLK1-DIO3 domain: a new link to prenatal and postnatal growth in humans. Am. J. Obstet. Gynecol. 217, 350.e1–350.e13 (2017).

  10. 10.

    Geach, T. DLK1 levels predict fetal growth restriction. Nat. Rev. Endocrinol. 13, 4–4 (2017).

  11. 11.

    Cacho, J., Sevillano, J., de Castro, J., Herrera, E. & Ramos, M. P. Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague-Dawley rats. Am. J. Physiol. Endocrinol. Metab. 295, E1269–E1276 (2008).

  12. 12.

    De Toro-Martín, J. et al. Predominant role of GIP in the development of a metabolic syndrome-like phenotype in female Wistar rats submitted to forced catch-up growth. Endocrinology 155, 3769–3780 (2014).

  13. 13.

    Turer, A. T. et al. Adipose tissue mass and location affect circulating adiponectin levels. Diabetologia 54, 2515–2524 (2011).

  14. 14.

    Berends, L. M., Fernandez-Twinn, D. S., Martin-Gronert, M. S., Cripps, R. L. & Ozanne, S. E. Catch-up growth following intra-uterine growth-restriction programmes an insulin-resistant phenotype in adipose tissue. Int J. Obes. 37, 1051–1057 (2012).

  15. 15.

    Lee, K. et al. Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1). J. Clin. Invest. 111, 453–461 (2003).

  16. 16.

    Villena, J. A., Kim, K. H. & Sul, H. S. Pref-1 and ADSF/resistin: two secreted factors inhibiting adipose tissue development. Horm. Metab. Res. 34, 664–670 (2002).

  17. 17.

    Bieswal, F. et al. The importance of catch-up growth after early malnutrition for the programming of obesity in male rat. Obesity 14, 1330–1343 (2006).

  18. 18.

    Duque-Guimarães, D. E. & Ozanne, S. E. Nutritional programming of insulin resistance: causes and consequences. Trends Endocrinol. Metab. 24, 525–535 (2013).

  19. 19.

    Somm, E. et al. Early metabolic defects in dexamethasone-exposed and undernourished intrauterine growth restricted rats. PLoS ONE 7, e50131 (2012).

  20. 20.

    Lafontan, M. Adipose tissue and adipocyte dysregulation. Diabetes Metab. 40, 16–28 (2014).

  21. 21.

    Kim, J. I. et al. Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation. Mol. Cell Biol. 35, 1686–1699 (2015).

  22. 22.

    Andersen, D. C. et al. Dual role of delta-like 1 homolog (DLK1) in skeletal muscle development and adult muscle regeneration. Development 140, 3743–3753 (2013).

  23. 23.

    Mullis, P.-E. & Tonella, P. Regulation of fetal growth: consequences and impact of being born small. Best. Pr. Res Clin. Endocrinol. Metab. 22, 173–190 (2008).

  24. 24.

    Gondret, F., Lefaucheur, L., Juin, H., Louveau, I. & Lebret, B. Low birth weight is associated with enlarged muscle fiber area and impaired meat tenderness of the longissimus muscle in pigs. J. Anim. Sci. 84, 93–103 (2006).

  25. 25.

    Ozanne, S. E. Metabolic programming in animals. Br. Med. Bull. 60, 143–152 (2001).

  26. 26.

    Cha, H. C. et al. Phosphorylation of CCAAT/enhancer-binding protein α regulates GLUT4 expression and glucose transport in adipocytes. J. Biol. Chem. 283, 18002–18011 (2008).

  27. 27.

    Amengual-Cladera, E., Lladó, I., Proenza, A. M. & Gianotti, M. Sex dimorphism in the onset of the white adipose tissue insulin sensitivity impairment associated with age. Biochimie 106, 75–80 (2014).

  28. 28.

    Guarda, D. S. et al. Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism. J. Nutr. Biochem. 35, 74–80 (2016).

  29. 29.

    Garcia-Carrizo, F., Priego, T., Szostaczuk, N., Palou, A. & Picó, C. Sexual dimorphism in the age-induced insulin resistance, liver steatosis, and adipose tissue function in rats. Front Physiol. 8, 445 (2017).

Download references

Acknowledgements

We would like to thank Dr. Glòria Oliveras Serrat and Ms. Yaiza Martin Gonzalez for the preparation of the tissue histological sections. The study was supported by grant no. PI13/01257 (to A.L.-B.) from the National Institute of Health Carlos III (Fund for Health Research FIS, Spain), project co-financed by FEDER.

Author information

All authors read and approved the final manuscript. G.C.-B., X.R., J.B. and A.L.-B. designed research; G.C.-B. and A.L.-B. wrote the first draft of the manuscript; G.C.-B., X.R. and A.P.-P. conducted research; G.C.-B., S.X.-T. and E.L.-M. analyzed data; and F.d.Z. and L.I. contributed to review the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Judit Bassols or Abel López-Bermejo.

Supplementary information

Supplementary Fig. S1

Supplementary Table S1

Supplementary Figure Legend

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2