Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling

β-cell adaptation to maternal insulin resistance of pregnancy involves up-regulation of β-cell mass and function, a process we previously showed depends on prolactin receptor (PRLR) signaling. Emering evidence in humans suggests that prolactin signaling may also influence β-cell function beyond pregnancy. This study aims to investigate how post-pregnancy metabolic stress - specifically the combined effects of prior pregnancy followed by high-fat diet (HFD) exposure - impacts β-cell function, with a focus on the role of PRLR. In this study, we found that multiparous transgenic female mice with β-cell-specific PRLR deletion (β Prlr -/- ) have impaired glucose tolerance when challenged with HFD. Unlike in pregnancy, where PRLR signaling up-regulates β-cell proliferation and mass, we observed no difference in β-cell mass between the wild type ( βPrlr +/+ ) and mutant ( βPrlr -/- ) mice when metabolically stressed with HFD. However, βPrlr -/- mice showed blunted first-phase insulin release in vivowhen challenged with glucose orally but not intraperitoneally, suggesting an impaired incretin effect. Moreover, there is a reduction in the expression of incretin hormone receptor, Glp-1r, and several of its upstream regulators, such as E2f1, Nkx6.1, Pax6, Pparγ, and Tcf7l2. Interestingly, isolated islets from βPrlr -/- mice showed intact in vitro glucose-stimulated insulin secretion (GSIS) but impaired incretin-potentiated GSIS. Islets from βPrlr -/- mice also had a lower insulin content and expressed lower levels of genes that regulate glucose metabolism. Together, these results suggested that PRLR signaling plays an important role in preserving β-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression and insulin secretory capacity in β-cells.