Maternal progesterone and adipose mPRε in pregnancy regulate the embryonic nutritional state

Sex steroid hormones such as progesterone play a pivotal role in reproductive functions and maintaining pregnancy; however, the impact of progesterone on the interaction between mother and embryo is unclear. Here, we demonstrate that the relationship between maternal progesterone and membrane progesterone receptor epsilon (mPRε) in adipose tissue regulates embryonic nutritional environment and growth after birth in mice. The activation of adipose mPRε by increased progesterone during pregnancy enhanced maternal insulin resistance through the production of prostaglandins by enhancing PLA2 activity, thereby efficiently providing glucose to embryos. The offspring of mPRε-deficient mothers exhibited metabolic dysfunction, whereas mPRε-deficient mothers with high-fat-diet-induced obesity exhibited improved insulin sensitivity. These findings establish the importance of progesterone as a nutritional regulator between mother and embryo and suggest that mPRε modulators could be developed to treat pregnant glycemic control disorders such as gestational diabetes mellitus, as well as metabolic syndrome in offspring.