High fat diet promotes obesity by driving miRNA dependent neurogenesis and integration of orexigenic neurons in the feeding circuitry

Abstract

A high-fat diet (HFD) regulates the feeding circuitry in young-adult mice by stimulating neurogenesis from {beta}2 tanycytes in the hypothalamus. However, the fate of HFD-induced tanycytic neurogenesis, the functional attributes of the nascent neurons, and mechanisms underlying their subsequent integration into the feeding-related neural circuitry remain unclear. microRNAs (miRNAs) are known to play crucial roles in adult neurogenesis. In this study, miRNA profiling of BrdU-labelled neurogenic {beta}2 tanycytes from HFD-fed mice identified a cohort of miRNAs that originate from different chromosomal loci rather than a single genomic cluster. Network analysis of predicted targets for these HFD-induced miRNAs identified key "hub" mRNA targets that influence neurogenesis and the functional integration of newborn neurons. These HFD-induced miRNAs promoted the differentiation of nascent neurons into orexigenic AgRP+ and anorexigenic POMC+ neurons. Interestingly, only AgRP+ newborn neurons were selectively integrated into the functional feeding circuit, as detected by c-Fos immunostaining. This integration was disrupted when HFD-induced miRNA activity was suppressed via hypothalamic miRNA sponge expression. Furthermore, HFD feeding increased body weight in female mice, which was abrogated upon the inhibition of HFD-induced miRNAs. Magnetic resonance imaging (MRI) revealed elevated liver fat in HFD-fed mice, which reverted to normal levels when the HFD-induced miRNAs in hypothalamic tanycytes were blocked. Collectively, the findings from our study highlight a miRNA-mediated paradigm that links HFD-induced neurogenesis from {beta}2 tanycytes to weight gain and liver fat accumulation, and identifies the selective integration of AgRP+ neurons into the feeding circuitry as a possible causality of HFD-induced changes to body weight. Significance StatementThis study highlights a miRNA-network that biases the transcriptional program in hypothalamic tanycytes to promote neurogenesis in young adult mice following their exposure to an acute high-fat diet (HFD) paradigm. These HFD-induced miRNAs have the potential to alter the brains feeding circuitry by promoting neurogenesis and the preferential functional integration of nascent orexigenic (AgRP+) neurons; resulting in weight gain and hepatic fat accumulation. Collective inhibition of this miRNA-network prevents the integration of newborn AgRP+ neurons and reverses the metabolic consequences of high-fat diet. Our study provides an unexplored link between diet, neurogenesis, and remodeling of the feeding circuitry; and reveals potential therapeutic targets for combating hyperphagic obesity.