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PGC-1α induced browning promotes involution and inhibits lactation in mammary glands

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Abstract

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.

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Abbreviations

PGC-1:

Peroxisome proliferator-activated receptor gamma coactivator 1

UCP1:

Uncoupling protein 1

TFAM:

Mitochondrial transcription factor A

Mmtv:

Mouse mammary tumor virus

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Acknowledgements

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.

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Author notes

  1. Elena Piccinin and Annalisa Morgano contributed equally.

Authors and Affiliations

  1. Department of Interdisciplinary Medicine, “Aldo Moro” University of Bari, Bari, Italy

    Elena Piccinin, Annalisa Morgano, Claudia Peres & Antonio Moschetta

  2. INBB, National Institute for Biostuctures and Biosystems, Rome, Italy

    Claudia Peres & Maria Arconzo

  3. Department of Neuroscience, Imaging and Clinical Sciences and Center for Research on Aging and Translational Medicine (CeSI-MeT), “G. d’Annunzio” University of Chieti, Chieti, Italy

    Annalisa Contursi

  4. MetaToul-Lipidomic Facility-MetaboHUB, INSERM UMR1048, Institute of Cardiovascular and Metabolic Diseases, Université Paul Sabatier, Toulouse, France

    Justine Bertrand-Michel

  5. Toxalim (Research Centre in Food Toxicology), Université de Toulouse, UMR1331 INRA, ENVT, INP-Purpan, Université Paul Sabatier, Toulouse, France

    Hervé Guillou

  6. Department of Basic Medical Sciences, Neurosciences and Sense Organs, “Aldo Moro” University of Bari, Bari, Italy

    Gaetano Villani

  7. National Cancer Center, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

    Antonio Moschetta

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  1. Elena Piccinin
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Contributions

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.

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Correspondence to Antonio Moschetta.

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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.

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18_2019_3160_MOESM1_ESM.tif

Supplementary Fig. 1 PGC-1α overexpression affects pups development. (A) hPGC-1α (white bars) and mPGC-1α (black bar) relative mRNA expression in different tissue specimens isolated from transgenic and wild type mice (n = 6) by real-time qPCR. TBP was used as housekeeping gene to normalize data and wild type mice was used as calibrators. Results are expressed as mean ± SEM. (B) Picture of wild-type and mmtvPGC-1α newborns at 21 days after birth. (C) Picture of wild type and mmtvPGC-1α newborns at 19 days after birth fostered by mmtvPGC-1α and wild-type mother, respectively. (TIFF 5283 kb)

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Piccinin, E., Morgano, A., Peres, C. et al. PGC-1α induced browning promotes involution and inhibits lactation in mammary glands. Cell. Mol. Life Sci. 76, 5011–5025 (2019). https://doi.org/10.1007/s00018-019-03160-y

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