MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies

Nutritional status during gestation may lead to a phenomenon known as metabolic programming, which can be triggered by epigenetic mechanisms. The Let-7 family of microRNAs were one of the first to be discovered, and are closely related to metabolic processes. Bioinformatic analysis revealed that Prkaa2, the gene that encodes AMPK alpha 2, is a predicted target of Let-7. Here we aimed to investigate whether Let-7 has a role in AMPK alpha 2 levels in the NAFLD development in the offspring programmed by maternal obesity. Let-7 levels were upregulated in the liver of newborn mice from obese dams, while the levels of Prkaa2 were downregulated. Let-7 levels strongly correlated with serum glucose, insulin and NEFA, and in vitro treatment of AML12 with glucose and NEFA lead to higher Let-7 expression. Transfection of Let-7a mimic lead to downregulation of AMPK alpha 2 levels, while the transfection with Let-7a inhibitor impaired both NEFA-mediated reduction of Prkaa2 levels and the fat accumulation driven by NEFA. The transfection of Let-7a inhibitor in ex-vivo liver slices from the offspring of obese dams restored phospho-AMPK alpha 2 levels. In summary, Let-7a appears to regulate hepatic AMPK alpha 2 protein levels and lead to the early hepatic metabolic disturbances in the offspring of obese dams. (AU)