During the prenatal development of mammals, the fetus resides in a low-glucose environment compared to the mother, a physiological gradient essential for transplacental glucose transfer. In spite of low glucose, it is essential to maintain an active anabolic metabolism to support rapid fetal growth. However, how fetal tissues sustain this anabolic metabolism remains unknown. Here, we observed surprisingly that in the fetal liver, mTORC1 — a central metabolic regulator that promotes anabolism — remains active in low glucose, a condition where it is typically inhibited, although AMPK, another metabolic regulator that promotes catabolism, is effectively activated in an AMP-dependent manner. Mechanistically, we discovered that the upstream regulator of mTORC1, TRPV4 (a key TRPV channel in the liver), is acetylated at K608, disabling its inactivation by fructose-1,6-bisphosphate (FBP)-unoccupied aldolase and blunting the inhibition of mTORC1 that usually occurs in low glucose. Expression of a non-acetylatable TRPV4-K608R mutant in fetal hepatocytes restores glucose sensitivity and inhibits mTORC1, and liver-specific expression of this mutant during embryonic development impairs hepatic anabolism, reduces fetal protein synthesis, and leads to intrauterine growth restriction or even death. Our findings reveal that resistance of mTORC1 to low glucose-induced inhibition mediated by TRPV acetylation acts as a safeguard for normal fetal development.
Zhang et al. (Thu,) studied this question.