Mammary adipocytes (blue cells) dedifferentiate into preadipocyte-like precursors during lactation. Image courtesy of Q. A. Wang and P. E. Scherer.

The origin of adipocytes in the mammary gland and mammary alveolar structures during pregnancy and lactation has been a matter of debate for some time. Various hypotheses have been put forward, including that mammary adipocytes transdifferentiate into mammary alveolar cells. In a new paper, Philipp Scherer and colleagues show that white adipocytes in the mammary gland dedifferentiate into precursor cells during pregnancy and lactation and then redifferentiate after weaning.

The researchers interbred three transgenic strains of mouse (including one expressing the LacZ reporter gene) to create a doxycycline-based tet-responsive Cre–loxP system, named AdipoChaser-LacZ. The mature adipocytes of these mice are permanently labelled, allowing their fate to be monitored over time. AdipoChaser-LacZ mice were bred, and mammary gland samples were collected during pregnancy, lactation and involution.

Scherer and colleagues found that none of the developing mammary gland structures stained positive for LacZ, which shows that these cells are not transdifferentiated from mature adipocytes. Importantly, they were also able to show that LacZ-positive adipocytes gradually lost their lipid droplets during lactation, so that they morphologically resembled fibroblasts. By the tenth day of lactation, these cells still stained positive for LacZ but were reduced in size and contained no lipid droplets. “The current text book suggests that fat cells only have three options: they can get bigger as we gain weight; they can get smaller as we lose weight; or they can die and cause inflammation,” says Scherer. “This paper shows for the first time that fat cells have an additional option: they can dedifferentiate.” After weaning, Scherer and co-workers found that adipocytes regenerated. These adipocytes were all positive for LacZ, indicating that they were derived from the original pool of mature adipocytes. Further experiments showed that these adipocytes dedifferentiated and redifferentiated through a second pregnancy.

“This dedifferentiation may also occur during weight loss and explain why fat cells ‘come back’ so easily,” concludes Scherer. “These cells stick with us for much longer than anticipated, and may disguise themselves as fibroblasts that are ready to come right back and turn into fat cells.”