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

Laís A P Simino,Murilo V Geraldo,Marcio A Torsoni,Letícia M Ignácio-Souza,Adriana S Torsoni,Thais De Fante,Marciane Milanski,Marina F Fontana,Michael G Ross,Carolina Panzarin,Mina Desai

doi:10.1038/s41598-021-88518-8

Abstract

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 α2, is a predicted target of Let-7. Here we aimed to investigate whether Let-7 has a role in AMPKα2 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 AMPKα2 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-AMPKα2 levels. In summary, Let-7a appears to regulate hepatic AMPKα2 protein levels and lead to the early hepatic metabolic disturbances in the offspring of obese dams.

Highlights

Nutritional status during gestation may lead to a phenomenon known as metabolic programming, which can be triggered by epigenetic mechanisms
We recently showed that offspring from obesity-prone (OP-O) dams fed high-fat diet as previously d escribed5 (HFD) during gestation demonstrated marked metabolic disturbances compared to offspring from obesity-resistant (OR-O) dams, with lower body weight at the delivery day (d0) being one of the main differences of obesityprone HFD-fed dams (OP-O) from OR-O14
AMPK is known as a cellular energy sensor, and its expression and activation have been largely studied as key mechanisms to prevent and treat metabolic abnormalities related to glucose and lipid homeostasis[11,12]

Summary

Introduction

Nutritional status during gestation may lead to a phenomenon known as metabolic programming, which can be triggered by epigenetic mechanisms. We aimed to investigate whether Let-7 has a role in AMPKα2 levels in the NAFLD development in the offspring programmed by maternal obesity. Transfection of Let-7a mimic lead to downregulation of AMPKα2 levels, while the transfection with Let-7a inhibitor impaired both NEFA-mediated reduction of Prkaa[2] levels and the fat accumulation driven by NEFA. Let-7a appears to regulate hepatic AMPKα2 protein levels and lead to the early hepatic metabolic disturbances in the offspring of obese dams. In the present study we sought to investigate whether hepatic Let-7 would have a role in the modulation of AMPKα2 in the context of the NAFLD development in the offspring programmed by maternal obesity during intrauterine life

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