Adiponectin: A prosurvival and proproliferation signal that increases bovine mammary epithelial cell numbers and protects them from endoplasmic reticulum stress responses

Cell-cell interactions between epithelial and stromal cells are predominant in the mammary gland, and various stromal cell-derived factors can elicit mitogenic responses in adjacent epithelial cells. Adiponectin is a hormone secreted mainly by adipocytes that mediates stromal-epithelial interactions in a number of tissues. Adiponectin receptors are expressed by bovine mammary epithelial cells, but the regulatory effects of adiponectin on the development and function of the mammary gland remain unclear. We therefore sought to investigate the effects of adiponectin on bovine mammary epithelial (MAC-T) cells and the regulatory mechanisms that underlie these adiponectin-induced actions. Our results revealed an increase in MAC-T cell proliferation and cell cycle progression in response to adiponectin. The expression of nuclear proliferating cell nuclear antigen (PCNA) and cyclin D1 was induced in MAC-T cells, and intracellular signaling molecules such as serine/threonine protein kinase (AKT), 70 kDa ribosomal S6 kinase (P70S6K), ribosomal protein S6 (S6), extracellular signal-regulated kinases 1 and 2 (ERK1/2), 90 kDa ribosomal S6 kinase (P90S6K), and cyclin D1 were activated in a dose-dependent manner. The abundance of adiponectin-induced signaling proteins was suppressed following inhibition of AKT or ERK1/2 mitogen-activated protein kinase (MAPK) signaling. In addition, inhibition of AKT or ERK1/2 signaling significantly reduced adiponectinstimulated MAC-T cell proliferation. Furthermore, adiponectin reduced tunicamycin-induced expression and activation of endoplasmic reticulum stress-related proteins in MAC-T cells and attenuated the repressive effect of tunicamycin on proliferation of MAC-T cells. Collectively, these results suggest that adiponectin-mediated signaling may affect the development and function of the mammary gland in dairy cows by increasing mammary epithelial cell numbers. These findings may result in important implications for improving our fundamental understanding of lactation physiology in livestock species.