Lipid-producing sebaceous glands (SGs) are essential for skin barrier function. They require constant replacement of SG cells (sebocytes) lost to holocrine secretion through progenitor cell populations. Disturbed SG maintenance is associated with various skin diseases, the pathways that govern SG morphogenesis and homeostasis are, however, still largely elusive. Here, we asked how epidermal Insulin/Insulin-like growth factor-1 (IGF-1) signalling (IIS) regulates SG development and homeostasis. We show that loss of both the insulin receptor and the IGF-1 receptor (IGF-1R) alone inhibits SG development, while complete IIS loss results in the absence of SGs at P0. SGs remain smaller in adult IGF-1R-/- mice. This correlates with a decreased proliferation of LRIG1+ sebocyte progenitor cells. Inducible loss of IGF-1R only in LRIG1+ cells also reduced SG size. Insulin/IGF-1 is furthermore essential for growth and proliferation of sebaceous organoids. IIS thus regulates SG development and homeostasis. We next asked which downstream factors transmit IIS in SGs. Epidermal loss of mTORC1 signalling components results in complete loss of sebocytes at P0, thus phenocopying loss of IIS, and mTOR inhibition reduces growth of sebaceous organoids. In contrast, epidermal loss of FoxO3 increases SG size, and a simultaneous loss of IGF-1R/FoxO1/FoxO3 rescues SG size in adult mice. Taken together, these results uncover a crucial role of IIS in SG development and homeostasis mediated by mTORC1 and FoxO signalling, and indicate that IIS promotes sebocyte progenitor proliferation. Whether IIS also determines sebocyte fate specification remains unclear and is investigated at present.

ESDR325 - Metabolic Signalling in Sebaceous Gland Development and Homeostasis

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING