Advertisement

Remodeling of Murine Mammary Adipose Tissue during Pregnancy, Lactation, and Involution

  • Qiong A. WangEmail author
  • Philipp E. SchererEmail author
Article
  • 19 Downloads

Abstract

White adipocytes in the mammary gland stroma comprise the majority of the mammary gland mass. White adipocytes regulate numerous hormonal and metabolic processes and exhibit compositional and phenotypic plasticity. This plasticity is exemplified by the ability of mammary adipocytes to regress during lactation, when mammary epithelial cells expand to establish sufficient milk-producing alveoli. Upon weaning, the process reverses through mammary involution, during which adipocytes extensively regenerate, and alveolar epithelial cells disappear through cell death, returning the mammary gland to the non-lactating state. Despite intensive studies on the development and involution of the mammary alveolar epithelium, the fate of mammary adipocytes during pregnancy and lactation, and the origins of mammary adipocytes regenerated during mammary involution, is poorly understood. Here, we discuss the recent discoveries of the fate of mammary adipocytes during pregnancy and lactation in a number of different mouse models, and the lineage origin of mammary adipocytes regenerated during involution.

Keywords

Adipocyte Mammary gland Lactation Involution Remodeling Dedifferentiation Obesity Breast Cancer 

Notes

Acknowledgments

P.E.S. is supported by US National Institutes of Health (NIH) grants R01-DK55758, P01-DK088761, R01-DK099110, RC2-DK118620, and P01-AG051459 and by an unrestricted grant from the Novo Nordisk Research Foundation. Q.A.W. is supported by National Institutes of Health (NIH) grants R56-AG063854 and R03-HD095414, American Diabetes Association Junior Faculty Development Award 1-19-JDF-023, as well as City of Hope Shared Resources Pilot Award and Caltech–City of Hope Initiative Award.

References

  1. 1.
    Landskroner-Eiger S, Park J, Israel D, Pollard JW, Scherer PE. Morphogenesis of the developing mammary gland: stage-dependent impact of adipocytes. Dev Biol. 2010;344(2):968–78.  https://doi.org/10.1016/j.ydbio.2010.06.019.Google Scholar
  2. 2.
    Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. Eur J Clin Investig. 2011;121(6):2094–101.  https://doi.org/10.1172/jci45887.Google Scholar
  3. 3.
    Rosen Evan D, Spiegelman BM. What We Talk About When We Talk About Fat. Cell. 156(1):20–44.  https://doi.org/10.1016/j.cell.2013.12.012.
  4. 4.
    Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol. 2015;208(5):501–12.  https://doi.org/10.1083/jcb.201409063.Google Scholar
  5. 5.
    Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 2019.  https://doi.org/10.1038/s41580-018-0093-z.
  6. 6.
    Rillema JA. Development of the mammary gland and lactation. Trends Endocrinol Metab. 1994;5(4):149–54.Google Scholar
  7. 7.
    Lund LR, Romer J, Thomasset N, Solberg H, Pyke C, Bissell MJ, et al. Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development. 1996;122(1):181–93.Google Scholar
  8. 8.
    Li M, Liu X, Robinson G, Bar-Peled U, Wagner KU, Young WS, et al. Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A. 1997;94(7):3425–30.Google Scholar
  9. 9.
    Richert MM, Schwertfeger KL, Ryder JW, Anderson SM. An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia. 2000;5(2):227–41.  https://doi.org/10.1023/A:1026499523505.Google Scholar
  10. 10.
    Eirew P, Stingl J, Raouf A, Turashvili G, Aparicio S, Emerman JT, et al. A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability. Nat Med. 2008;14(12):1384–9 http://www.nature.com/nm/journal/v14/n12/suppinfo/nm.1791_S1.html.Google Scholar
  11. 11.
    Tiede B, Kang Y. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. Cell Res. 2011;21(2):245–57.  https://doi.org/10.1038/cr.2011.11.Google Scholar
  12. 12.
    Lloyd-Lewis B, Harris OB, Watson CJ, Davis FM. Mammary stem cells: premise, properties, and perspectives. Trends Cell Biol. 2017;27(8):556–67.  https://doi.org/10.1016/j.tcb.2017.04.001.Google Scholar
  13. 13.
    Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature. 2011;479:189.  https://doi.org/10.1038/nature10573 https://www.nature.com/articles/nature10573#supplementary-information.Google Scholar
  14. 14.
    Lafkas D, Rodilla V, Huyghe M, Mourao L, Kiaris H, Fre S. Notch3 marks clonogenic mammary luminal progenitor cells in vivo. J Cell Biol. 2013;203(1):47–56.  https://doi.org/10.1083/jcb.201307046.Google Scholar
  15. 15.
    Chang THT, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM. New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res. 2014;16(1):R1.  https://doi.org/10.1186/bcr3593.Google Scholar
  16. 16.
    Prater MD, Petit V, Alasdair Russell I, Giraddi RR, Shehata M, Menon S, et al. Mammary stem cells have myoepithelial cell properties. Nat Cell Biol. 2014;16:942.  https://doi.org/10.1038/ncb3025 https://www.nature.com/articles/ncb3025#supplementary-information.Google Scholar
  17. 17.
    Rodilla V, Dasti A, Huyghe M, Lafkas D, Laurent C, Reyal F, et al. Luminal progenitors restrict their lineage potential during mammary gland development. PLoS Biol. 2015;13(2):e1002069.  https://doi.org/10.1371/journal.pbio.1002069.Google Scholar
  18. 18.
    Wuidart A, Ousset M, Rulands S, Simons BD, Van Keymeulen A, Blanpain C. Quantitative lineage tracing strategies to resolve multipotency in tissue-specific stem cells. Genes Dev. 2016;30(11):1261–77.  https://doi.org/10.1101/gad.280057.116.Google Scholar
  19. 19.
    Joshi PA, Waterhouse PD, Kasaian K, Fang H, Gulyaeva O, Sul HS, et al. PDGFRα+ stromal adipocyte progenitors transition into epithelial cells during lobulo-alveologenesis in the murine mammary gland. Nat Commun. 2019;10(1):1760.  https://doi.org/10.1038/s41467-019-09748-z.Google Scholar
  20. 20.
    Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat M-L, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439(7072):84–8 http://www.nature.com/nature/journal/v439/n7072/suppinfo/nature04372_S1.html.Google Scholar
  21. 21.
    Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, et al. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439(7079):993–7.  https://doi.org/10.1038/nature04496.Google Scholar
  22. 22.
    van Amerongen R, Bowman Angela N, Nusse R. Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell. 2012;11(3):387–400.  https://doi.org/10.1016/j.stem.2012.05.023.Google Scholar
  23. 23.
    Rios AC, Fu NY, Lindeman GJ, Visvader JE. In situ identification of bipotent stem cells in the mammary gland. Nature. 2014;506:322.  https://doi.org/10.1038/nature12948 https://www.nature.com/articles/nature12948#supplementary-information.Google Scholar
  24. 24.
    Wang D, Cai C, Dong X, Yu QC, Zhang XO, Yang L, et al. Identification of multipotent mammary stem cells by protein C receptor expression. Nature. 2015;517(7532):81–4.  https://doi.org/10.1038/nature13851.Google Scholar
  25. 25.
    Davis FM, Lloyd-Lewis B, Harris OB, Kozar S, Winton DJ, Muresan L, et al. Single-cell lineage tracing in the mammary gland reveals stochastic clonal dispersion of stem/progenitor cell progeny. Nat Commun. 2016;7:13053.  https://doi.org/10.1038/ncomms13053 https://www.nature.com/articles/ncomms13053#supplementary-information.Google Scholar
  26. 26.
    Morroni M, Giordano A, Zingaretti MC, Boiani R, De Matteis R, Kahn BB, et al. Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland. Proc Natl Acad Sci U S A. 2004;101(48):16801–6.  https://doi.org/10.1073/pnas.0407647101.Google Scholar
  27. 27.
    Prokesch A, Smorlesi A, Perugini J, Manieri M, Ciarmela P, Mondini E, et al. Molecular aspects of adipoepithelial transdifferentiation in mouse mammary gland. Stem Cells. 2014;32(10):2756–66.  https://doi.org/10.1002/stem.1756.Google Scholar
  28. 28.
    Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19(10):1338–44.  https://doi.org/10.1038/nm.3324.Google Scholar
  29. 29.
    Wang QA, Song A, Chen W, Schwalie PC, Zhang F, Vishvanath L, Jiang L, Ye R, Shao M, Tao C, Gupta RK, Deplancke B, Scherer PE. Reversible De-differentiation of Mature White Adipocytes into Preadipocyte-like Precursors during Lactation. Cell Metabolism. 2018;28(2):282–8.e3.  https://doi.org/10.1016/j.cmet.2018.05.022.
  30. 30.
    Zwick RK, Rudolph MC, Shook BA, Holtrup B, Roth E, Lei V, et al. Adipocyte hypertrophy and lipid dynamics underlie mammary gland remodeling after lactation. Nat Commun. 2018;9(1):–3592.  https://doi.org/10.1038/s41467-018-05911-0.
  31. 31.
    Jena MK, Jaswal S, Kumar S, Mohanty AK. Molecular mechanism of mammary gland involution: An update. Dev Biol. 2019;445(2):145–55.  https://doi.org/10.1016/j.ydbio.2018.11.002.Google Scholar
  32. 32.
    Stein T, Salomonis N, Gusterson BA. Mammary gland involution as a multi-step process. J Mammary Gland Biol Neoplasia. 2007;12(1):25–35.  https://doi.org/10.1007/s10911-007-9035-7.Google Scholar
  33. 33.
    Jena MK, Jaswal S, Kumar S, Mohanty AK. Molecular mechanism of mammary gland involution: An update. Dev Biol. 2019;445(2):145–55.  https://doi.org/10.1016/j.ydbio.2018.11.002.Google Scholar
  34. 34.
    Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150(6):1223–34.Google Scholar
  35. 35.
    Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature. 2013;503(7475):218.Google Scholar
  36. 36.
    Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9(18):2266–78 Epub 1995/09/15.Google Scholar
  37. 37.
    Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl. Acad. Sci. U. S. A. 1998;95(9):5076–81.Google Scholar
  38. 38.
    Neville MC, McFadden TB, Forsyth I. Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia. 2002;7(1):49–66.Google Scholar
  39. 39.
    Kelly PA, Bachelot A, Kedzia C, Hennighausen L, Ormandy CJ, Kopchick JJ, et al. The role of prolactin and growth hormone in mammary gland development. Mol Cell Endocrinol. 2002;197(1–2):127–31.Google Scholar
  40. 40.
    Clegg RA. Lipoprotein lipase. Localization on plasma membrane fragments from lactating rat mammary tissue. Biochim Biophys Acta. 1981;664(2):397–408.  https://doi.org/10.1016/0005-2760(81)90062-x.Google Scholar
  41. 41.
    Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of Obesity Among Adults and Youth: United States, 2015-2016. NCHS Data Brief. 2017;(288):1–8.Google Scholar
  42. 42.
    Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1–2):20–44.  https://doi.org/10.1016/j.cell.2013.12.012.Google Scholar
  43. 43.
    Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov. 2016;15(9):639–60.  https://doi.org/10.1038/nrd.2016.75.Google Scholar
  44. 44.
    Crewe C, An YA, Scherer PE. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest. 2017;127(1):74–82.  https://doi.org/10.1172/JCI88883.Google Scholar
  45. 45.
    Hilson JA, Rasmussen KM, Kjolhede CL. High prepregnant body mass index is associated with poor lactation outcomes among white, rural women independent of psychosocial and demographic correlates. Journal of human lactation : official journal of International Lactation Consultant Association. 2004;20(1):18–29.  https://doi.org/10.1177/0890334403261345.Google Scholar
  46. 46.
    Rasmussen KM. Association of Maternal Obesity before Conception with poor lactation performance. Annu Rev Nutr. 2007;27(1):103–21.  https://doi.org/10.1146/annurev.nutr.27.061406.093738.Google Scholar
  47. 47.
    Jevitt C, Hernandez I, Groer M. Lactation complicated by overweight and obesity: supporting the mother and newborn. J Midwifery Womens Health. 2007;52(6):606–13.  https://doi.org/10.1016/j.jmwh.2007.04.006.Google Scholar
  48. 48.
    Rasmussen KM. Association of maternal obesity before conception with poor lactation performance. Annu Rev Nutr. 2007;27:103–21.Google Scholar
  49. 49.
    Chu SY, Bachman DJ, Callaghan WM, Whitlock EP, Dietz PM, Berg CJ, et al. Association between obesity during pregnancy and increased use of health care. N Engl J Med. 2008;358(14):1444–53.  https://doi.org/10.1056/NEJMoa0706786.Google Scholar
  50. 50.
    Davies GA, Maxwell C, McLeod L, Gagnon R, Basso M, Bos H, et al. Obesity in pregnancy. Int J Gynecol Obstet. 2010;110(2):167–73.Google Scholar
  51. 51.
    Riddle SW, Nommsen-Rivers LA. A case control study of diabetes during pregnancy and low milk supply. Breastfeed Med. 2016;11(2):80–5.Google Scholar
  52. 52.
    Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356.  https://doi.org/10.1136/bmj.j1.
  53. 53.
    Stuebe AM, Rich-Edwards JW, Willett WC, Manson JE, Michels KB. Duration of lactation and incidence of type 2 diabetes. Jama. 2005;294(20):2601–10.  https://doi.org/10.1001/jama.294.20.2601.Google Scholar
  54. 54.
    Schwarz EB, Brown JS, Creasman JM, Stuebe A, McClure CK, Van Den Eeden SK, Thom D. Lactation and maternal risk of type 2 diabetes: a population-based study. Am J Med. 2010;123(9):863. e1-. e6.Google Scholar
  55. 55.
    Ziegler A-G, Wallner M, Kaiser I, Rossbauer M, Harsunen MH, Lachmann L, et al. Long-term protective effect of lactation on the development of type 2 diabetes in women with recent gestational diabetes mellitus. Diabetes. 2012;61(12):3167–71.Google Scholar
  56. 56.
    Arenz S, Ruckerl R, Koletzko B, von Kries R. Breast-feeding and childhood obesity--a systematic review. Int J Obes Relat Metab Disord. 2004;28(10):1247–56.  https://doi.org/10.1038/sj.ijo.0802758.Google Scholar
  57. 57.
    Organization WH. Exclusive Breastfeeding to Reduce the Risk of Childhood Overweight and Obesity 2004.Google Scholar
  58. 58.
    Martin RM, Gunnell D, Davey SG. Breastfeeding in infancy and blood pressure in later life: systematic review and meta-analysis. Am J Epidemiol. 2005;161(1):15–26.Google Scholar
  59. 59.
    Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics. 2005;115(5):1367–77.Google Scholar
  60. 60.
    Owen CG, Martin RM, Whincup PH, Davey-Smith G, Gillman MW, Cook DG. The effect of breastfeeding on mean body mass index throughout life: a quantitative review of published and unpublished observational evidence. Am J Clin Nutr. 2005;82(6):1298–307.Google Scholar
  61. 61.
    Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr. 2006;84(5):1043–54.Google Scholar
  62. 62.
    Quigley MA. Re: "duration of breastfeeding and risk of overweight: a meta-analysis". Am J Epidemiol. 2006;163(9):870–2; author reply 2-3.  https://doi.org/10.1093/aje/kwj134.Google Scholar
  63. 63.
    Owen CG, Whincup PH, Kaye SJ, Martin RM, Davey Smith G, Cook DG, et al. Does initial breastfeeding lead to lower blood cholesterol in adult life? A quantitative review of the evidence. Am J Clin Nutr. 2008;88(2):305–14.Google Scholar
  64. 64.
    Savino F, Liguori SA, Fissore MF, Oggero R. Breast milk hormones and their protective effect on obesity. Int J Pediatr Endocrinol. 2009;2009(1):327505.Google Scholar
  65. 65.
    Bernardo H, Cesar V, Organization, WH. Long-term effects of breastfeeding: a systematic review 2013.Google Scholar
  66. 66.
    Hovey RC, Aimo L. Diverse and active roles for adipocytes during mammary gland growth and function. J Mammary Gland Biol Neoplasia. 2010;15(3):279–90.Google Scholar
  67. 67.
    Schedin P, Keely PJ. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb Perspect Biol. 2011;3(1):a003228.Google Scholar
  68. 68.
    Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature. 2011;479(7372):189.Google Scholar
  69. 69.
    Macias H, Hinck L. Mammary gland development. Wiley Interdiscip Rev Dev Biol. 2012;1(4):533–57.Google Scholar
  70. 70.
    Inman JL, Robertson C, Mott JD, Bissell MJ. Mammary gland development: cell fate specification, stem cells and the microenvironment. Development. 2015;142(6):1028–42.Google Scholar
  71. 71.
    Akers RM. Lactation and the mammary gland: John Wiley & Sons; 2016.Google Scholar
  72. 72.
    Flint DJ, Travers MT, Barber MC, Binart N, Kelly PA. Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland. Am J Physiol Endocrinol Metab. 2005;288(6):E1179–E87.  https://doi.org/10.1152/ajpendo.00433.2004.Google Scholar
  73. 73.
    Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;331(1):5–9.  https://doi.org/10.1056/nejm199407073310102.Google Scholar
  74. 74.
    Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6(4):281–91.  https://doi.org/10.1038/nrc1839.Google Scholar
  75. 75.
    Stensheim H, Møller B, van Dijk T, Fosså SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27(1):45–51.Google Scholar
  76. 76.
    Park J, Scherer PE. Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest. 2012;122(11):4243–56.  https://doi.org/10.1172/JCI63930.Google Scholar
  77. 77.
    Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, et al. JAK/STAT3-Regulated Fatty Acid beta-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metab. 2018;27(6):1357.  https://doi.org/10.1016/j.cmet.2018.04.018.Google Scholar
  78. 78.
    Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer--mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10(8):455–65.  https://doi.org/10.1038/nrendo.2014.94.Google Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Molecular & Cellular EndocrinologyDiabetes and Metabolism Research Institute, City of HopeDuarteUSA
  2. 2.Comprehensive Cancer Center, Beckman Research InstituteCity of HopeDuarteUSA
  3. 3.Touchstone Diabetes CenterUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations