Gestational diabetes mellitus (GDM) is characterized by fasting hyperglycemia and glucose intolerance during pregnancy, but with poorly understood mechanisms. We found that prolactin receptor (Prlr) is markedly upregulated in liver of pregnant female mice. These findings have spurred the hypothesis that hepatic Prlr signaling is pivotal for physiological adaptation of hepatic metabolism to gestation. To address this hypothesis, we generated liver-conditional L-Prlr-KO mice, followed by determination of glucose and lipid metabolism in female L-Prlr-KO vs. age-matched female WT mice prior to and during gestation. Hepatic Prlr depletion did not impact glucose and lipid metabolism in virgin L-Prlr-KO mice. However, pregnant L-Prlr-KO mice developed GDM, as evidenced by the induction of glucose intolerance, fasting hyperglycemia, higher HOMA-IR levels and abnormal glucose-stimulated insulin secretion at gestational day 15.5. We reproduced these findings in female L-Prlr-KO mice in the 1st, 2nd and 3rd pregnancy, with the severity of GDM exacerbated by transient high fat feeding prior to conception in female L-Prlr-KO mice. Hepatic Prlr depletion did not affect litter size, but pups born to L-Prlr-KO mice had significantly lower birth weight. We recapitulated this finding in newborns derived from the 1st, 2nd and 3rd pregnancy in L-Prlr-KO mice. Hepatic Prlr depletion also resulted in increased triglyceride and cholesterol levels in liver, characteristic of nonalcoholic fatty liver disease and consistent with increased insulin resistance in pregnant L-Prlr-KO mice. Multiparous L-Prlr-KO mice developed postpartum prediabetes. Our studies unveiled an unprecedented role of hepatic Prlr signaling in regulating maternal hepatic metabolism to protect against GDM.
C. Zhu: None. J. Yamauchi: None. C. Pan: None. J. Gao: None. S. Qu: None. R.R. Banerjee: None. H. Dong: None.
National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677)