Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food

Abstract

In utero exposure to maternal obesity programs a susceptibility to develop obesity. Animal models have shown that offspring obesity is often preceded by increased food intake, however, the mechanisms that mediate these changes are not understood. Using a mouse model of maternal diet-induced obesity we observed increased intake specifically of a high-fat pellet in adult offspring of obese mothers. Through small RNA sequencing, we identified programmed overexpression of miR-505-5p in the hypothalamus of offspring of obese mothers that is established in the fetus, and confirmed in vitro that fatty acid exposure increases expression of miR-505-5p. Pulsed SILAC analysis demonstrated protein targets of miR-505-5p are enriched in pathways involved in fatty acid metabolism. These include key components of neuronal fatty acid sensing, such as Cpt1a, that are implicated in BMI regulation in human genetic studies. Over-expression of miR-505-5p decreased neuronal fatty acid uptake and metabolism in vitro. Importantly, intra-cerebroventricular injection of a miR-505-5p mimic in mice resulted in increased high-fat pellet intake. Collectively these data suggest that maternal obesity induces over-expression of miR-505-5p in offspring hypothalamus, resulting in altered fatty acid sensing and increased intake of high-fat diet. This represents a novel mechanism by which maternal obesity programs obesity in offspring.

Early life impacts of maternal obesity: a window of opportunity to improve the health of two generations

“…Our group has shown that programmed cell-autonomous upregulation of miR-126 in adipose tissue of offspring of obese mothers is responsible for downregulation of insulin receptor substrate 1 and lunapark, contributing to insulin resistance [ 55 ] and ER stress [ 56 ] in these animals. We have also shown that exposure to maternal obesity causes upregulation of miR-505-5p in the fetal hypothalamus, and downregulation of targets that are related to fatty acid sensing pathways [ 57 ]. Over-expression of miR-505-5p in the adult mouse brain causes increased intake of a high-fat diet, suggesting that programmed over-expression of this miRNA after exposure to maternal obesity could underlie altered food choices in offspring that lead to obesity.…”