PGC-1α induced browning promotes involution and inhibits lactation in mammary glands
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The PPARγ coactivator 1α (PGC-1α) is a transcriptional regulator of mitochondrial biogenesis and oxidative metabolism. Recent studies have highlighted a fundamental role of PGC-1α in promoting breast cancer progression and metastasis, but the physiological role of this coactivator in the development of mammary glands is still unknown. First, we show that PGC-1α is highly expressed during puberty and involution, but nearly disappeared in pregnancy and lactation. Then, taking advantage of a newly generated transgenic mouse model with a stable and specific overexpression of PGC-1α in mammary glands, we demonstrate that the re-expression of this coactivator during the lactation stage leads to a precocious regression of the mammary glands. Thus, we propose that PGC-1α action is non-essential during pregnancy and lactation, whereas it is indispensable during involution. The rapid preadipocyte–adipocyte transition, together with an increased rate of apoptosis promotes a premature mammary glands involution that cause lactation defects and pup growth retardation. Overall, we provide new insights in the comprehension of female reproductive cycles and lactation deficiency, thus opening new roads for mothers that cannot breastfeed.
KeywordsMammary glands Nuclear receptor Coactivator Development Adipocytes Involution
Peroxisome proliferator-activated receptor gamma coactivator 1
Uncoupling protein 1
Mitochondrial transcription factor A
Mouse mammary tumor virus
We thank L. Salvatore and G. Di Tullio, for their invaluable help during the study, and J-M. Lobaccaro and J. Hardfeldth, for their help with the manuscript. A. Moschetta is funded by Italian Association for Cancer Research (AIRC, IG 18987), NR-NET FP7 Marie Curie People ITN and EU-JPI FATMAL 2017.
EP contributed to study design, performed experiments, analysed data and wrote the paper; AM contributed to study design, performed experiments and data analysis; CP, AC, JBM, MA and HG performed experiments; GV contributed to paper writing; AM designed the study, supervised the project and paper writing.
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interests.
The Ethical Committee of the Consorzio Mario Negri Sud and the University of Bari approved this experimental set-up, which also was certified by the Italian Ministry of Health in accordance with internationally accepted guidelines for animal care.
- 2.Neville MC (1999) Physiology of lactation. Clin Perinatol 26(251–79):vGoogle Scholar
- 7.Morroni M, Giordano A, Zingaretti MC, Boiani R, De MR, Kahn BB, Nisoli E, Tonello C, Pisoschi C, Luchetti MM, Marelli M, Cinti S (2004) Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland. Proc Natl Acad Sci USA 101:16801–16806Google Scholar
- 21.LeBleu VS, O’Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, Asara JM, Kalluri R (2014) PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16:992–1003PubMedPubMedCentralGoogle Scholar
- 24.Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De MR, Cinti S (2010) The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab 298:E1244–E1253PubMedGoogle Scholar
- 28.Straub BK, Gyoengyoesi B, Koenig M, Hashani M, Pawella LM, Herpel E, Mueller W, Macher-Goeppinger S, Heid H, Schirmacher P (2013) Adipophilin/perilipin-2 as a lipid droplet-specific marker for metabolically active cells and diseases associated with metabolic dysregulation. Histopathology 62:617–631PubMedGoogle Scholar
- 29.Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359Google Scholar
- 40.Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM (2012) A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468PubMedPubMedCentralGoogle Scholar
- 44.Jones LP, Buelto D, Tago E, Owusu-Boaitey KE (2011) Abnormal mammary adipose tissue environment of Brca1 mutant mice show a persistent deposition of highly vascularized multilocular adipocytes. J Cancer Sci Ther (Suppl 2):004Google Scholar
- 48.Lord SJ, Bernstein L, Johnson KA, Malone KE, McDonald JA, Marchbanks PA, Simon MS, Strom BL, Press MF, Folger SG, Burkman RT, Deapen D, Spirtas R, Ursin G (2008) Breast cancer risk and hormone receptor status in older women by parity, age of first birth, and breastfeeding: a case-control study. Cancer Epidemiol Biomark Prev 17:1723–1730Google Scholar