Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food
Year: 2024
Type: article
Abstract: In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.
Source: PLoS Biology
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,500
Funders: Wellcome Trust, British Society for Neuroendocrinology, British Heart Foundation, Royal Society, Coventry University, Fundação de Amparo à Pesquisa do Estado de São Paulo, Fundação de Amparo à Pesquisa do Estado da Bahia, Medical Research Council, Biotechnology and Biological Sciences Research Council
Awards: G1460824713, G1956948480, G2496626792, G2892497062, G2899719236, Early life origins of obesity: developmental programming of hypothalamic development and function., G323977781, G3261240233, G3572101131, Central nervous system as a target of growth hormone for the regulation of multiple biological functions, Insulin and hypoxia: key determinants in the programming of cardiovascular disease by maternal obesity, G5353444125, G5517677352, Targeting macrophage lipid metabolism to dissociate obesity from cardiovascular risk (renewal), G603945095, G611623758, ADIPOSE TISSUE DYSFUNCTION AND LIPOTOXICITY, G7786739171, G8401366047, Child Growth and development, G9000353250, G953086832
OpenAlex ID: W4399324362