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Neonatal leptin antagonism improves metabolic programming of postnatally overnourished mice

Abstract

Background/Objectives

Alteration of the perinatal nutritional environment is an important risk factor for the development of metabolic diseases in later life. The hormone leptin plays a critical role in growth and development. Previous studies reported that postnatal overnutrition increases leptin secretion during the pre-weaning period. However, a direct link between leptin, neonatal overnutrition, and lifelong metabolic regulation has not been investigated.

Methods

We used the small litter mouse model combined with neonatal leptin antagonist injections to examine whether attenuating leptin during early life improves lifelong metabolic regulation in postnatally overnourished mice.

Results

Postnatally overnourished mice displayed rapid weight gain during lactation and remained overweight as adults. These mice also showed increased adiposity and perturbations in glucose homeostasis in adulthood. Neonatal administration of a leptin antagonist normalized fat mass and insulin sensitivity in postnatally overnourished mice. These metabolic improvements were associated with enhanced sensitivity of hypothalamic neurons to leptin.

Conclusions

Early postnatal overnutrition causes metabolic alterations that can be permanently attenuated with the administration of a leptin antagonist during a restricted developmental window.

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Fig. 1: Neonatal leptin antagonism improves body composition without affecting growth in neonatally overnourished mice.
Fig. 2: Neonatal leptin antagonism causes a shift in adipocyte size distribution in neonatally overfed mice.
Fig. 3: Neonatal leptin antagonism reverses alterations in glucose metabolism in neonatally overfed mice.
Fig. 4: Neonatal overnutrition causes central leptin resistance that can be improved with leptin antagonist.

References

  1. Rogers I. The influence of birthweight and intrauterine environment on adiposity and fat distribution in later life. Int J Obes Rel Metabol Disord. 2003;27:755–77.

    Article  Google Scholar 

  2. Cruz ML, Shaibi GQ, Weigensberg MJ, Spruijt-Metz D, Ball GDC, Goran MI. Pediatric obesity and insulin resistance: chronic disease risk and implications for treatment and prevention beyond body weight modification. Ann Rev Nutr. 2005;25:435–68.

    CAS  Article  Google Scholar 

  3. Plagemann A. Perinatal nutrition and hormone-dependent programming of food intake. Hormone Res. 2006;65:83–89.

    CAS  PubMed  Article  Google Scholar 

  4. McMillen IC, Adam CL, Muhlhausler BS. Early origins of obesity: programming the appetite regulatory system. J Physiol. 2005;565:9–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Taylor PD, Poston L. Developmental programming of obesity in mammals. Exp Physiol. 2007;92:287–98.

    CAS  PubMed  Article  Google Scholar 

  6. Martin-Gronert MS, Ozanne SE. Programming of appetite and type 2 diabetes. Early Hum Dev. 2005;81:981–8.

    CAS  PubMed  Article  Google Scholar 

  7. Bouret S, Levin BE, Ozanne SE. Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. Physiol Rev. 2015;95:47–82.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Kennedy GC. The development with age of hypothalamic restraint upon the appetite of the rat. J Endocrinol. 1957;16:9/17.

    Article  Google Scholar 

  9. Widdowson EM, Mc CR. Some effects of accelerating growth. I. General somatic development. Proc R Soc Lond B Biol Sci. 1960;152:188–206.

    CAS  PubMed  Article  Google Scholar 

  10. Knittle JL, Hirsch J. Effect of early nutrition on the development of rat epididymal fat pads: cellularity and metabolism. J Clin Invest. 1968;47:2091–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Collden G, Balland E, Parkash J, Caron E, Langlet F, Prevot V, et al. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Molecular Metabolism. 2015;4:15–24.

    CAS  PubMed  Article  Google Scholar 

  12. Kayser BD, Goran MI, Bouret SG. Perinatal overnutrition exacerbates adipose tissue inflammation caused by high-fat feeding in C57BL/6J mice. PLoS One. 2015;10:e0121954.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Davidowa H, Plagemann A. Insulin resistance of hypothalamic arcuate neurons in neonatally overfed rats. Neuroreport. 2007;18:521–4.

    CAS  PubMed  Article  Google Scholar 

  14. Rodrigues AL, De Souza EP, Da Silva SV, Rodrigues DS, Nascimento AB, Barja-Fidalgo C, et al. Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition. J Endocrinol. 2007;195:485–94.

    CAS  PubMed  Article  Google Scholar 

  15. Glavas MM, Kirigiti MA, Xiao XQ, Enriori PJ, Fisher SK, Evans AE, et al. Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet. Endocrinology. 2010;151:1598–610.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Yzydorczyk C, Li N, Rigal E, Chehade H, Mosig D, Armengaud JB, et al. Calorie restriction in adulthood reduces hepatic disorders induced by transient postnatal overfeeding in mice. Nutrients. 2019;11:2796.

    CAS  PubMed Central  Article  Google Scholar 

  17. Ahima R, Prabakaran D, Flier J. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest. 1998;101:1020–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Ahima RS, Hileman SM. Postnatal regulation of hypothalamic neuropeptide expression by leptin: implications for energy balance and body weight regulation. Regul Pept. 2000;92:1–7.

    CAS  PubMed  Article  Google Scholar 

  19. Proulx K, Richard D, Walker C-D. Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. Endocrinology. 2002;143:4683–92.

    CAS  PubMed  Article  Google Scholar 

  20. Mistry A, Swick A, Romsos D. Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice. Am J Physiol. 1999;277:R742–747.

    CAS  PubMed  Google Scholar 

  21. Schmidt I, Fritz A, Scholch C, Schneider D, Simon E, Plagemann A. The effect of leptin treatment on the development of obesity in overfed suckling Wistar rats. Int J Obes Rel Metabol Disord. 2001;25:1168–74.

    CAS  Article  Google Scholar 

  22. Bouret SG. Neurodevelopmental actions of leptin. Brain Res. 2010;350:2–9.

    Article  CAS  Google Scholar 

  23. Granado M, Fuente-Martín E, García-Cáceres C, Argente J, Chowen JA. Leptin in early life: a key factor for the development of the adult metabolic profile. Obes Facts. 2012;5:138–50.

    CAS  PubMed  Article  Google Scholar 

  24. Briffa JF, McAinch AJ, Romano T, Wlodek ME, Hryciw DH. Leptin in pregnancy and development: a contributor to adulthood disease? Am J Physiol Endocrinol Metabol. 2015;308:E335–E350.

    CAS  Article  Google Scholar 

  25. Davidowa H, Plagemann A. Decreased inhibition by leptin of hypothalamic arcuate neurons in neonatally overfed young rats. Neuroreport. 2000;11:2795–8.

    CAS  PubMed  Article  Google Scholar 

  26. Marangon PB, Mecawi AS, Antunes-Rodrigues J, Elias LLK. Perinatal over- and underfeeding affect hypothalamic leptin and ghrelin neuroendocrine responses in adult rats. Physiol Behav. 2020;215:112793.

    CAS  PubMed  Article  Google Scholar 

  27. Coupe B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metabol. 2012;15:247–55.

    CAS  Article  Google Scholar 

  28. Habbout A, Li N, Rochette L, Vergely C. Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences. J Nutr. 2013;143:553–62.

    CAS  PubMed  Article  Google Scholar 

  29. Plagemann A, Harder T, Rake A, Melchior K, Rohde W. D√∂rner Gn. Increased number of galanin-neurons in the paraventricular hypothalamic nucleus of neonatally overfed weanling rats. Brain Res. 1999;818:160–3.

    CAS  PubMed  Article  Google Scholar 

  30. Shpilman M, Niv-Spector L, Katz M, Varol C, Solomon G, Ayalon-Soffer M, et al. Development and characterization of high affinity leptins and leptin antagonists. J Biol Chem. 2011;286:4429–42.

    CAS  PubMed  Article  Google Scholar 

  31. Elinav E, Niv-Spector L, Katz M, Price TO, Ali M, Yacobovitz M, Solomon G, Reicher S, Lynch JL, Halpern Z, Banks WA, Gertler A. Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity. Endocrinology. 2009;150:3083–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Hou M, Liu Y, Zhu L, Sun B, Guo M, Burén J, et al. Neonatal overfeeding induced by small litter rearing causes altered glucocorticoid metabolism in rats. PLoS One. 2011;6:e25726.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. López M, Seoane LM, Tovar S, García MC, Nogueiras R, Diéguez C, et al. A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat. Diabetologia. 2005;48:140–8.

    PubMed  Article  CAS  Google Scholar 

  34. Ziko I, Sominsky L, Nguyen T-X, Yam K-Y, De Luca S, Korosi A, et al. Hyperleptinemia in neonatally overfed female rats does not dysregulate feeding circuitry. Front Endocrinol. 2017;8:287–287.

    Article  Google Scholar 

  35. Rodrigues AL, de Moura EG, Passos MC, Trevenzoli IH, da Conceição EP, Bonono IT, et al. Postnatal early overfeeding induces hypothalamic higher SOCS3 expression and lower STAT3 activity in adult rats. J Nutr Biochem. 2011;22:109–17.

    CAS  PubMed  Article  Google Scholar 

  36. Kappeler L, De Magalhaes Filho C, Leneuve P, Xu J, Brunel N, Chatziantoniou C, et al. Early postnatal nutrition determines somatotropic function in mice. Endocrinology. 2009;150:314–23.

    CAS  PubMed  Article  Google Scholar 

  37. Boullu-Ciocca S, Dutour A, Guillaume V, Achard V, Oliver C, Grino M. Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome. Diabetes. 2005;54:197–203.

    CAS  PubMed  Article  Google Scholar 

  38. Cunha AC, Pereira RO, Pereira MJ, Soares Vde M, Martins MR, Teixeira MT, et al. Long-term effects of overfeeding during lactation on insulin secretion-the role of GLUT-2. J Nutr Biochem. 2009;20:435–42.

    CAS  PubMed  Article  Google Scholar 

  39. Plagemann A, Harder T, Rake A, Voits M, Fink H, Rohde W, et al. Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Res. 1999;836:146–55.

    CAS  PubMed  Article  Google Scholar 

  40. Boullu-Ciocca S, Achard V, Tassistro V, Dutour A, Grino M. Postnatal programming of glucocorticoid metabolism in rats modulates high-fat diet-induced regulation of visceral adipose tissue glucocorticoid exposure and sensitivity and adiponectin and proinflammatory adipokines gene expression in adulthood. Diabetes. 2008;57:669–77.

    CAS  PubMed  Article  Google Scholar 

  41. Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, et al. Neonatal leptin treatment reverses developmental programming. Endocrinology. 2005;146:4211–6.

    CAS  PubMed  Article  Google Scholar 

  42. Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, et al. The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy. Endocrinology. 2008;149:1906–13.

    CAS  PubMed  Article  Google Scholar 

  43. Hoggard N, Hunter L, Lea R, Trayhurn P, Mercer J. Ontogeny of the expression of leptin and its receptor in the murine fetus and placenta. Br J Nutr. 2000;83:317–26.

    CAS  PubMed  Article  Google Scholar 

  44. Caron E, Sachot C, Prevot V, Bouret SG. Distribution of leptin-sensitive cells in the postnatal and adult mouse brain. J Comp Neurol. 2010;518:459–76.

    CAS  PubMed  Article  Google Scholar 

  45. Bouret SG, Draper SJ, Bates SH, Kirigiti MA, Chen S, Bjornholm M, et al. Leptin promotes formation of projection pathways from the arcuate nucleus of the hypothalamus through activation of ObRb signaling pathways In Proceedings of the 34nd Annual Meeting The Society For Neuroscience, San Diego, CA. 2004.

  46. Bouret SG, Bates SH, Chen S, Myers MG, Simerly RB. Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits. J Neurosci. 2012;32:1244–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Islam M, Sjoholm A, Emilsson V. Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells. Int J Obes Relat Metab Disord. 2000;24:1246–53.

    CAS  PubMed  Article  Google Scholar 

  48. Croizier S, Prevot V, Bouret Sebastien G. Leptin controls parasympathetic wiring of the pancreas during embryonic life. Cell Rep. 2016;15:36–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Attig L, Larcher T, Gertler A, Abdennebi-Najar L, Djiane J. Postnatal leptin is necessary for maturation of numerous organs in newborn rats. Organogenesis. 2011;7:88–94.

    PubMed  PubMed Central  Article  Google Scholar 

  50. Attig L, Brisard D, Larcher T, Mickiewicz M, Guilloteau P, Boukthir S, et al. Postnatal leptin promotes organ maturation and development in IUGR piglets. PLoS One. 2013;8:e64616.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Chen X, Lin J, Hausman DB, Martin RJ, Dean RG, Hausman GJ. Alterations in fetal adipose tissue leptin expression correlate with the development of adipose tissue. Neonatology. 2000;78:41–47.

    CAS  Article  Google Scholar 

  52. Aprath-Husmann I, Rohrig K, Gottschling-Zeller H, Skurk T, Scriba D, Birgel M, et al. Effects of leptin on the differentiation and metabolism of human adipocytes. Int J Obesity Rel Metab Disord. 2001;25:1465–70.

    CAS  Article  Google Scholar 

  53. Hayashida T, Nakahara K, Mondal MS, Date Y, Nakazato M, Kojima M, et al. Ghrelin in neonatal rats: distribution in stomach and its possible role. J Endocrinol. 2002;173:239–45.

    CAS  PubMed  Article  Google Scholar 

  54. Pinilla L, Barreiro ML, Tena-Sempere M, Aguilar E. Role of ghrelin in the control of growth hormone secretion in prepubertal rats: interactions with excitatory amino acids. Neuroendocrinology. 2003;77:83–90.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

This work was supported by a research grant from the Inserm (grant 1172, to SGB). We thank the mouse metabolic phenotyping and cellular imaging cores of the UMS2014-US41 for accessing the metabolic cages and confocal microscope, respectively.

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GC and SGB conceived and designed the project. GC performed experiments. SGB, GC, and EC analyzed data. GC and SGB wrote the manuscript. All the authors read and approved the manuscript.

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Correspondence to Sebastien G. Bouret.

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Colldén, G., Caron, E. & Bouret, S.G. Neonatal leptin antagonism improves metabolic programming of postnatally overnourished mice. Int J Obes 46, 1138–1144 (2022). https://doi.org/10.1038/s41366-022-01093-4

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