Hepatic Let-7 modulation and the effects on energy homeostasis on offspring programmed by maternal obesity

Obesity has reached alarming rates in recent years. In women, besides being associated with increased obstetric risks, this condition is closely related to fetal metabolic programming and to the perpetuation of obesity and metabolic diseases. Metabolic programming may originate from epigenetic changes, such as modulation of microRNAs (miRs) expression. One of the first miRs to be discovered, Let-7, along with Lin28 protein, participates in the regulation of various biological processes, including energy metabolism. Previous work from our group has shown that offspring of mice programmed by maternal obesity during pregnancy and lactation present higher body weight and several metabolic disturbances. Given that epigenome programming occurs during critical developmental periods, our hypothesis was that maternal obesity could modulate the Let-7/Lin28 axis in the liver of mice offspring that this modulation could be related to changes in the homeostasis energy of these animals. We performed in silico analysis and identified that Let-7a has as predicted target the gene that encodes the AMPK protein (Prkaa2). We then subjected female mice to 4 weeks of high calorie diet (HC) and subdivided them into obesity resistant (OR) or obesity prone (OP). OP females had higher body weight, glycemia, insulinemia, cholesterol and free fatty acids (NEFA) compared to control females (C). Females were mated with control male and the offspring were evaluated at the delivery day (d0) and after weaning (d28). The data show that deleterious metabolic effects are more pronounced in OP offspring compared to OR. OP offspring showed increased Let-7a levels and decreased hepatic Prkaa2 at both d0 and d28. We investigated which maternal conditions would be involved with Let-7 modulation and identified that NEFA, glucose and TNF? are able to modulate Let-7a levels in hepatocytes. We transfected hepatocytes with Let-7a mimic and observed decreased AMPK content, while Let-7a inhibitor transfection restored Prkaa2 levels and fat accumulation caused by NEFA treatment. Ex vivo transfection with Let-7a inhibitor restored LIN28 and pAMPK levels in the liver of OP offspring. Thus, the results show that the deleterious effects of metabolic programming are more pronounced when the dam fed HC diet develops obesity and metabolic disorders in the pre-gestational period. Furthermore, the potential Let-7/AMPK axis may be related with the metabolic disorders observed in the offspring of obese dams (AU)