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

Cell Mol Life Sci. 2019 Dec;76(24):5011-5025. doi: 10.1007/s00018-019-03160-y. Epub 2019 Jun 1.

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.

Keywords: Adipocytes; Coactivator; Development; Involution; Mammary glands; Nuclear receptor.

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Apoptosis / genetics
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Humans
  • Lactation / genetics*
  • Lactation / metabolism
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Transgenic
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Pregnancy

Substances

  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse