pp 1–10 | Cite as

Early weaning leads to specific glucocorticoid signalling in fat depots of adult rats

  • Rosiane Aparecida Miranda
  • Carla Bruna Pietrobon
  • Iala Milene Bertasso
  • Vanessa S. Tavares Rodrigues
  • Bruna Pereira Lopes
  • Camila Calvino
  • Elaine de Oliveira
  • Egberto Gaspar de Moura
  • Patrícia C. LisboaEmail author
Original Article



Early weaning (EW) is a stressful condition that programmes a child to be overweight in adult life. Fat mass depends on glucocorticoids (GC) to regulate adipogenesis and lipogenesis. We hypothesised that the increased adiposity in models of EW was due to a disturbed HPA axis and/or disrupted GC function.


We used two experimental models, pharmacological early weaning (PEW, dams were bromocriptine-treated) and non-pharmacological early weaning (NPEW, dams’ teats were wrapped with a bandage), which were initiated during the last 3 days of lactation. Offspring from both genders was analysed on postnatal day 180.


Offspring in both models were overweight with increased visceral fat mass, but plasma corticosterone was increased in both genders in the PEW group but not the NPEW group. NPEW males had increased GRα expression in visceral adipose tissue (VAT), and GRα expression decreased in PEW males in subcutaneous adipose tissue (SAT). Females in both EW groups had increased 11βHSD1 expression in SAT. PEW males had increased C/EBPβ expression in SAT. PEW females had lower PPARy and FAS expression in VAT than the NPEW females. We detected a sex dimorphism in VAT and SAT in the EW groups regarding 11βHSD1, GRα and C/EBPβ expression.


The accumulated adiposity induced by EW exhibited distinct mechanisms depending on gender, specific fat deposition and GC metabolism and action. The higher proportion of VAT/SAT in both sets of EW males may be related to the action of GC in these tissues, and the higher conversion of GC in SAT in females may explain the differences in the fat distribution.


Early weaning Glucocorticoids Adipogenesis and lipogenesis 



All authors are grateful to Mr Ulisses Risso Siqueira for animal care and to Mrs Fabiana Gallaulckydio for technical assistance.


This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Estado do Rio de Janeiro (FAPERJ) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The Institutional Ethical Committee for the use of laboratory animals of the Biology Institute, State University of Rio de Janeiro approved all experimental procedures (CEUA/035/2017). This article does not contain any studies with human participants performed by any of the authors.


  1. 1.
    M. Agosti, F. Tandoi, L. Morlacchi, A. Bossi, Nutritional and metabolic programming during the first thousand days of life. Med. Surg. Pediatr. 39(2), 157 (2017). Google Scholar
  2. 2.
    D.J. Barker, The origins of the developmental origins theory. J. Intern. Med. 261(5), 412–417 (2007). CrossRefGoogle Scholar
  3. 3.
    F. Mosca, M.L. Gianni, Human milk: composition and health benefits. Med. Surg. Pediatr. 39(2), 155 (2017). Google Scholar
  4. 4.
    E. Rouw, A. von Gartzen, A. Weissenborn, [The importance of breastfeeding for the infant]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 61(8), 945–951 (2018). CrossRefGoogle Scholar
  5. 5.
    WHO/UNICEF, Global Strategy for Infant and Young Child Feeding. (World Health Organization, Geneva, 2003).Google Scholar
  6. 6.
    T. Harder, R. Bergmann, G. Kallischnigg, A. Plagemann, Duration of breastfeeding and risk of overweight: a meta-analysis. Am. J. Epidemiol. 162(5), 397–403 (2005). CrossRefGoogle Scholar
  7. 7.
    I.T. Bonomo, P.C. Lisboa, A.R. Pereira, M.C. Passos, E.G. de Moura, Prolactin inhibition in dams during lactation programs for overweight and leptin resistance in adult offspring. J. Endocrinol. 192(2), 339–344 (2007). CrossRefGoogle Scholar
  8. 8.
    S. Lima Nda, E.G. de Moura, M.C. Passos, F.J. Nogueira Neto, A.M. Reis, E. de Oliveira, P.C. Lisboa, Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br. J. Nutr. 105(9), 1405–1413 (2011). CrossRefGoogle Scholar
  9. 9.
    N.S. Lima, E.G. Moura, J.G. Franco, C.R. Pinheiro, C.C. Pazos-Moura, A. Cabanelas, A.S. Carlos, C.C. Nascimento-Saba, E. de Oliveira, P.C. Lisboa, Developmental plasticity of endocrine disorders in obesity model primed by early weaning in dams. Horm. Metab. Res. 45(1), 22–30 (2013). Google Scholar
  10. 10.
    E.G. de Moura, I.T. Bonomo, J.F. Nogueira-Neto, E. de Oliveira, I.H. Trevenzoli, A.M. Reis, M.C. Passos, P.C. Lisboa, Maternal prolactin inhibition during lactation programs for metabolic syndrome in adult progeny. J. Physiol. 587(Pt 20), 4919–4929 (2009). CrossRefGoogle Scholar
  11. 11.
    A.L. Fowden, O.A. Valenzuela, O.R. Vaughan, J.K. Jellyman, A.J. Forhead, Glucocorticoid programming of intrauterine development. Domest. Anim. Endocrinol. 56(Suppl), S121–S132 (2016). CrossRefGoogle Scholar
  12. 12.
    K.G. Stenkula, C. Erlanson-Albertsson, Adipose cell size: importance in health and disease. American journal of physiology. Regulatory Integr. Comp. Physiol. 315(2), R284–R295 (2018). CrossRefGoogle Scholar
  13. 13.
    K. John, J.S. Marino, E.R. Sanchez, T.D. Hinds Jr, The glucocorticoid receptor: cause of or cure for obesity? Am. J. Physiol. Endocrinol. Metab. 310(4), E249–E257 (2016). CrossRefGoogle Scholar
  14. 14.
    Y.K. Park, K. Ge, Glucocorticoid receptor accelerates, but is dispensable for, adipogenesis. Mol. Cell. Biol. 37(2) (2017).
  15. 15.
    J.J. Tomlinson, A. Boudreau, D. Wu, E. Atlas, R.J. Hache, Modulation of early human preadipocyte differentiation by glucocorticoids. Endocrinology 147(11), 5284–5293 (2006). CrossRefGoogle Scholar
  16. 16.
    B. Legeza, P. Marcolongo, A. Gamberucci, V. Varga, G. Banhegyi, A. Benedetti, A. Odermatt, Fructose, glucocorticoids and adipose tissue: implications for the metabolic syndrome. Nutrients 9(5) (2017).
  17. 17.
    J.E. Campbell, A.J. Peckett, A. D’Souza, T.J. Hawke, M.C. Riddell, Adipogenic and lipolytic effects of chronic glucocorticoid exposure. Am. J. Physiol. Cell Physiol. 300(1), C198–C209 (2011). CrossRefGoogle Scholar
  18. 18.
    L.L. Gathercole, S.A. Morgan, I.J. Bujalska, D. Hauton, P.M. Stewart, J.W. Tomlinson, Regulation of lipogenesis by glucocorticoids and insulin in human adipose tissue. PLoS ONE 6(10), e26223 (2011). CrossRefGoogle Scholar
  19. 19.
    A.T. Ali, W.E. Hochfeld, R. Myburgh, M.S. Pepper, Adipocyte and adipogenesis. Eur. J. cell Biol. 92(6-7), 229–236 (2013). CrossRefGoogle Scholar
  20. 20.
    C. Pantoja, J.T. Huff, K.R. Yamamoto, Glucocorticoid signaling defines a novel commitment state during adipogenesis in vitro. Mol. Biol. Cell 19(10), 4032–4041 (2008). CrossRefGoogle Scholar
  21. 21.
    H.S. Abdou, E. Atlas, R.J. Hache, A positive regulatory domain in CCAAT/enhancer binding protein beta (C/EBPBeta) is required for the glucocorticoid-mediated displacement of histone deacetylase 1 (HDAC1) from the C/ebpalpha promoter and maximum adipogenesis. Endocrinology 154(4), 1454–1464 (2013).–2061 CrossRefGoogle Scholar
  22. 22.
    A.J. Peckett, D.C. Wright, M.C. Riddell, The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism. 60(11), 1500–1510 (2011). CrossRefGoogle Scholar
  23. 23.
    P.P. Nunes, S. Andreotti, F. de Fatima Silva, R.A.L. Sertie, R.O. Caminhotto, A.C.M. Komino, G.B. Reis, F.B. Lima, Chronic low-dose glucocorticoid treatment increases subcutaneous abdominal fat, but not visceral fat, of male Wistar rats. Life Sci. 190, 29–35 (2017). CrossRefGoogle Scholar
  24. 24.
    R. Quinn, Comparing rat’s to human’s age: how old is my rat in people years? Nutrition 21(6), 775–777 (2005). CrossRefGoogle Scholar
  25. 25.
    V.S.T. Rodrigues, E.G. Moura, D.N. Bernardino, J.C. Carvalho, P.N. Soares, T.C. Peixoto, N. Peixoto-Silva, E. Oliveira, P.C. Lisboa, Supplementation of suckling rats with cow’s milk induces hyperphagia and higher visceral adiposity in females at adulthood, but not in males. J. Nutr. Biochem. 55, 89–103 (2018). CrossRefGoogle Scholar
  26. 26.
    G. Vitellius, S. Trabado, J. Bouligand, B. Delemer, M. Lombes, Pathophysiology of Glucocorticoid Signaling. Ann. d.’endocrinologie 79(3), 98–106 (2018). CrossRefGoogle Scholar
  27. 27.
    E.S. van der Valk, M. Savas, E.F.C. van Rossum, Stress and obesity: are there more susceptible individuals? Curr. Obes. Rep. 7(2), 193–203 (2018). CrossRefGoogle Scholar
  28. 28.
    M.M. Ibrahim, Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11(1), 11–18 (2010). CrossRefGoogle Scholar
  29. 29.
    B.L. Wajchenberg, Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr. Rev. 21(6), 697–738 (2000). CrossRefGoogle Scholar
  30. 30.
    J. Liu, C.S. Fox, D.A. Hickson, W.D. May, K.G. Hairston, J.J. Carr, H.A. Taylor, Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. J. Clin. Endocrinol. Metab. 95(12), 5419–5426 (2010). CrossRefGoogle Scholar
  31. 31.
    C.S. Fox, J.M. Massaro, U. Hoffmann, K.M. Pou, P. Maurovich-Horvat, C.Y. Liu, R.S. Vasan, J.M. Murabito, J.B. Meigs, L.A. Cupples, R.B.,Sr D’Agostino, C.J. O’Donnell, Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116(1), 39–48 (2007). CrossRefGoogle Scholar
  32. 32.
    J.J. Lee, A. Pedley, K.E. Therkelsen, U. Hoffmann, J.M. Massaro, D. Levy, M.T. Long, Upper body subcutaneous fat is associated with cardiometabolic risk factors. Am. J. Med. 130(8), 958–966 e951 (2017). CrossRefGoogle Scholar
  33. 33.
    J.J. Lee, K.A. Britton, A. Pedley, J.M. Massaro, E.K. Speliotes, J.M. Murabito, U. Hoffmann, C. Ingram, J.F. Jr. Keaney, R.S. Vasan, C.S. Fox, Adipose tissue depots and their cross-sectional associations with circulating biomarkers of metabolic regulation. J Am Heart Assoc. 5(5) (2016).
  34. 34.
    A. Passaro, M.A. Miselli, J.M. Sanz, E. Dalla Nora, M.L. Morieri, R. Colonna, R. Pisot, G. Zuliani, Gene expression regional differences in human subcutaneous adipose tissue. BMC Genomics 18(1), 202 (2017). CrossRefGoogle Scholar
  35. 35.
    S. Baglioni, G. Cantini, G. Poli, M. Francalanci, R. Squecco, A. Di Franco, E. Borgogni, S. Frontera, G. Nesi, F. Liotta, M. Lucchese, G. Perigli, F. Francini, G. Forti, M. Serio, M. Luconi, Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS ONE 7(5), e36569 (2012). CrossRefGoogle Scholar
  36. 36.
    X. Ma, P. Lee, D.J. Chisholm, D.E. James, Control of adipocyte differentiation in different fat depots; implications for pathophysiology or therapy. Front. Endocrinol. 6, 1 (2015). Google Scholar
  37. 37.
    C. Asensio, P. Muzzin, F. Rohner-Jeanrenaud, Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance. Int. J. Obes. Relat. Metab. Disord. 28(Suppl 4), S45–S52 (2004). CrossRefGoogle Scholar
  38. 38.
    A.B. Chapman, D.M. Knight, G.M. Ringold, Glucocorticoid regulation of adipocyte differentiation: hormonal triggering of the developmental program and induction of a differentiation-dependent gene. J. cell Biol. 101(4), 1227–1235 (1985)CrossRefGoogle Scholar
  39. 39.
    R.A. Lee, C.A. Harris, J.C. Wang, Glucocorticoid receptor and adipocyte biology. Nuclear Recept. Res. 5 (2018).
  40. 40.
    M.C. Fraga, E.G. Moura, J.O. Silva, I.T. Bonomo, C.C. Filgueiras, Y. Abreu-Villaca, M.C. Passos, P.C. Lisboa, A.C. Manhaes, Maternal prolactin inhibition at the end of lactation affects learning/memory and anxiety-like behaviors but not novelty-seeking in adult rat progeny. Pharmacol. Biochem. Behav. 100(1), 165–173 (2011). CrossRefGoogle Scholar
  41. 41.
    M.J. Lee, S.K. Fried, The glucocorticoid receptor, not the mineralocorticoid receptor, plays the dominant role in adipogenesis and adipokine production in human adipocytes. Int. J. Obes. 38(9), 1228–1233 (2014). CrossRefGoogle Scholar
  42. 42.
    A. Hermanowski-Vosatka, J.M. Balkovec, K. Cheng, H.Y. Chen, M. Hernandez, G.C. Koo, C.B. Le Grand, Z. Li, J.M. Metzger, S.S. Mundt, H. Noonan, C.N. Nunes, S.H. Olson, B. Pikounis, N. Ren, N. Robertson, J.M. Schaeffer, K. Shah, M.S. Springer, A.M. Strack, M. Strowski, K. Wu, T. Wu, J. Xiao, B.B. Zhang, S.D. Wright, R. Thieringer, 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J. Exp. Med. 202(4), 517–527 (2005). CrossRefGoogle Scholar
  43. 43.
    H. Masuzaki, H. Yamamoto, C.J. Kenyon, J.K. Elmquist, N.M. Morton, J.M. Paterson, H. Shinyama, M.G. Sharp, S. Fleming, J.J. Mullins, J.R. Seckl, J.S. Flier, Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J. Clin. Investig. 112(1), 83–90 (2003). CrossRefGoogle Scholar
  44. 44.
    S. Engeli, J. Bohnke, M. Feldpausch, K. Gorzelniak, U. Heintze, J. Janke, F.C. Luft, A.M. Sharma, Regulation of 11beta-HSD genes in human adipose tissue: influence of central obesity and weight loss. Obes. Res. 12(1), 9–17 (2004). CrossRefGoogle Scholar
  45. 45.
    A. Armani, V. Marzolla, G. Rosano, M. Caprio, Mineralocorticoid vs glucocorticoid receptors: solo players or team mates in the control of adipogenesis? Int. J. Obes. 38(12), 1580–1581 (2014). CrossRefGoogle Scholar
  46. 46.
    M. Sekiya, N. Yahagi, T. Matsuzaka, Y. Takeuchi, Y. Nakagawa, H. Takahashi, H. Okazaki, Y. Iizuka, K. Ohashi, T. Gotoda, S. Ishibashi, R. Nagai, T. Yamazaki, T. Kadowaki, N. Yamada, J. Osuga, H. Shimano, SREBP-1-independent regulation of lipogenic gene expression in adipocytes. J. lipid Res. 48(7), 1581–1591 (2007). CrossRefGoogle Scholar
  47. 47.
    G.J. Darlington, S.E. Ross, O.A. MacDougald, The role of C/EBP genes in adipocyte differentiation. J. Biol. Chem. 273(46), 30057–30060 (1998)CrossRefGoogle Scholar
  48. 48.
    A.R. Proenca, R.A. Sertie, A.C. Oliveira, A.B. Campana, R.O. Caminhotto, P. Chimin, F.B. Lima, New concepts in white adipose tissue physiology. Braz. J. Med. Biol. Res. 47(3), 192–205 (2014)CrossRefGoogle Scholar
  49. 49.
    F.J. Ortega, D. Mayas, J.M. Moreno-Navarrete, V. Catalan, J. Gomez-Ambrosi, E. Esteve, J.I. Rodriguez-Hermosa, B. Ruiz, W. Ricart, B. Peral, G. Fruhbeck, F.J. Tinahones, J.M. Fernandez-Real, The gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue of obese subjects. Obesity 18(1), 13–20 (2010). CrossRefGoogle Scholar
  50. 50.
    M.S. Gauthier, J.R. Perusse, M.E. Lavoie, R. Sladek, S.R. Madiraju, N.B. Ruderman, B. Coulombe, M. Prentki, R. Rabasa-Lhoret, Increased subcutaneous adipose tissue expression of genes involved in glycerolipid-fatty acid cycling in obese insulin-resistant versus -sensitive individuals. J. Clin. Endocrinol. Metab. 99(12), E2518–E2528 (2014). CrossRefGoogle Scholar
  51. 51.
    L. Penicaud, P. Ferre, F. Assimacopoulos-Jeannet, D. Perdereau, A. Leturque, B. Jeanrenaud, L. Picon, J. Girard, Increased gene expression of lipogenic enzymes and glucose transporter in white adipose tissue of suckling and weaned obese Zucker rats. Biochem. J. 279(Pt 1), 303–308 (1991)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Rosiane Aparecida Miranda
    • 1
  • Carla Bruna Pietrobon
    • 1
  • Iala Milene Bertasso
    • 1
  • Vanessa S. Tavares Rodrigues
    • 1
  • Bruna Pereira Lopes
    • 1
  • Camila Calvino
    • 1
  • Elaine de Oliveira
    • 1
  • Egberto Gaspar de Moura
    • 1
  • Patrícia C. Lisboa
    • 1
    Email author
  1. 1.Laboratory of Endocrine Physiology, Biology InstituteRio de Janeiro State UniversityRio de JaneiroBrazil

Personalised recommendations