SUMMARY Prenatal development may adopt unique patterns of metabolic responses to different nutrient supplies. AMPK and mTOR are two central metabolic regulators, with AMPK acting to slow down and mTOR to promote anabolism. Typically, low glucose inhibits TRPVs, leading to AMPK activation and mTOR complex I (mTORC1) inhibition. Here, we observed surprisingly that mTORC1 in the foetal liver remains active in low glucose, although AMPK is effectively activated in an AMP-dependent manner. Mechanistically, we found that TRPV4, a key liver TRPV, is acetylated at K608, disabling its inactivation by fructose-1,6-bisphosphate (FBP)-unoccupied aldolase. Mutation of K608 to arginine renders TRPV4 able to respond to low glucose in foetal hepatocytes. Consistently, embryonic liver-specific expression of acetylation-defective TRPV4-K608R mutant led to mTORC1 inhibition, and caused abnormal intrauterine development or even foetal death. Our findings reveal that the TRPV-mediated resistance of mTORC1 inhibition in low glucose acts as a safeguard for normal foetal development.
Zhang et al. (Thu,) studied this question.