Molecular aspects of adipoepithelial transdifferentiation in mouse mammary gland.

The circular, reversible conversion of the mammary gland during pregnancy and involution is a paradigm of physiological tissue plasticity. The two most prominent cell types in mammary gland, adipocytes and epithelial cells, interact in an orchestrated way to coordinate this process. Previously, we showed that this conversion is at least partly achieved by reciprocal transdifferentiation between mammary adipocytes and lobulo-alveolar epithelial cells. Here, we aim to shed more light on the regulators of mammary transdifferentiation. Using immunohistochemistry with cell type-specific lipid droplet-coating markers (Perilipin1 and 2), we show that cells with an intermediate adipoepithelial phenotype exist during and after pregnancy. Nuclei of cells with similar transitional structural characteristics are highly positive for Elf5, a master regulator of alveologenesis. In cultured adipocytes, we could show that transient and stable ectopic expression of Elf5 induces expression of the milk component whey acidic protein, although the general adipocyte phenotype is not affected suggesting that additional pioneering factors are necessary. Furthermore, the lack of transdifferentiation of adipocytes during pregnancy after clearing of the epithelial compartment indicates that transdifferentiation signals must emanate from the epithelial part. To explore candidate genes potentially involved in the transdifferentiation process, we devised a high-throughput gene expression study to compare cleared mammary fat pads with developing, contralateral controls at several time points during pregnancy. Incorporation of bioinformatic predictions of secretory proteins provides new insights into possible paracrine signaling pathways and downstream transdifferentiation factors. We discuss a potential role for osteopontin (secreted phosphoprotein 1 [Spp1]) signaling through integrins to induce adipoepithelial transdifferentiation.

Morphological and immunohistochemical features of brown adipocytes and preadipocytes in a case of human hibernoma.

BACKGROUND AND AIM: The role of brown adipose tissue physiology and pathology in humans is debated. A greater knowledge of its developmental aspects could play a pivotal role in devising treatments for obesity and diabetes. METHODS AND RESULTS: Tissue from a rare case of hibernoma, removed from a 17-year-old boy, was examined by light and electron microscopy, morphometry and immunohistochemistry. The tumour was well vascularised and innervated and contained mature adipocytes with the characteristics of both brown and white adipocytes. Numerous, poorly differentiated cells resembling brown adipocyte precursors were seen in a pericytic position in close association with the capillary wall. On immunohistochemistry mature brown adipocytes were seen to express the marker protein UCP1. On morphometry the intensity of uncoupling protein 1 (UCP1) immunostaining varied in relation to the morphological features of adipocytes: the "whiter" their appearance, the weaker their UCP1 immunoreactivity. CONCLUSIONS: Our data suggest that in humans, as in rodents, brown adipocyte precursors arise in close association with vessel walls and that intermediate forms between white and brown adipocytes can also be documented in human adults.