Placental miR-340 mediates vulnerability to activity based anorexia in mice
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ABSTRACT: Anorexia nervosa (AN) is a devastating eating disorder characterized by self-starvation that mainly affects women. Its etiology is unknown, which impedes successful treatment options leading to a limited chance of full recovery. Here, we show that gestation is a vulnerable window that can influence the predisposition to AN. By screening placental microRNA expression of naive and prenatally stressed (PNS) fetuses and assessing vulnerability to activity-based anorexia (ABA) in early adulthood, we identify miR-340 as a sexually dimorphic regulator involved in prenatal programming of ABA. PNS caused gene-body hypermethylation of placental miR-340, which is associated with reduced miR-340 expression and increased protein levels of several target transcripts; Gr, Cry2 and H3F3b. MiR-340 is linked to the expression of several nutrient transporters both in mice and human placentas. Using placenta-specific lentiviral transgenes and embryo transfer, we demonstrate the key role miR-340 plays in the mechanism involved in early life programming of ABA.
Project description:Anorexia nervosa (AN) is a complex debilitating disease characterized by intense fear of weight gain and excessive exercise. It is the deadliest of any psychiatric disorder with a high rate of recidivism, yet its pathophysiology is unclear. The Activity-Based Anorexia (ABA) paradigm is a widely accepted mouse model of AN that recapitulates hypophagia and hyperactivity despite reduced body weight, however, not the chronicity. Here, we modified the prototypical ABA paradigm to increase the time to lose 25% of baseline body weight from less than 7 days to more than 2 weeks. We used this paradigm to identify persistently altered genes after weight restoration that represent a metabolic memory of under-nutrition and may contribute to AN relapse. We focused on adipose tissue as it was identified as a major location of metabolic memory of over-nutririon. We identified 300 persistently dysregulated genes, including Calm2 and Vps13d, which could be potential global regulators of metabolic memory in both chronic over- and under-nutrition. However, despite being on the opposite spectrum of weight perturbations, the majority of metabolic memory genes of under- and over-nutrition do not overlap, suggestive of the different mechanisms involved in these extreme nutritional statuses.
Project description:As part of the Genetic Consortium for Anorexia Nervosa (GCAN) and Wellcome Trust Case
Control Consortium 3 (WTCCC3), we have amassed the largest anorexia nervosa (AN)
sample in the world (~4,000). Following the WTCCC3 GWAS, we secured funding from the
Klarman Family Foundation to extend the genetic analyses to variants on the exome chip
(CoreExome array). This pre-lim relates to carrying out genotyping on the CoreExome array
on up to a maximum of 580 new samples.
Project description:To identify functional targets of miR-340, we compared the gene expression profiles of miR-340 overexpressing human GICs with the profiles of their parental cells. The precursor form of miR-340 or control miRNA was overexpressed in glioma cells using miRNA lentiviral particles. The cells were incubated with recombinant virus at 37°C for 12 hr and cultured in the presence of puromycin for 3 days.
Project description:To identify functional targets of miR-340, we compared the gene expression profiles of miR-340 overexpressing human GICs with the profiles of their parental cells.