Endocrine Abstracts

In utero exposure to maternal obesity programs an increased risk of 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 remains to adulthood and confirmed in vitro that fatty acid exposure increases expression of miR-505-5p in hypothalamic neurons. 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 pathways. Over-expression of miR-505-5p decreased neuronal fatty acid uptake and metabolism in neurons in vitro. Importantly, intra-cerebroventricular injection of a miR-505-5p mimic in mice resulted in increased intake specifically of a high-fat pellet. 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 exposure to obesity in pregnancy programs obesity in offspring.