INTRODUCTION: MicroRNAs (miRNAs) are essential post-transcriptional regulators of gene expression, particularly in the central nervous system. The RNase III enzyme Dicer is critical for the maturation of miRNAs. Conditional deletion of the Dicer1 gene in the hypothalamus has been shown to result in hyperphagic obesity in mice, implicating miRNA pathways in the regulation of energy homeostasis. We hypothesize that the transient nature of obesity observed in hypothalamic Dicer-deficient mice is driven by compensatory neurogenesis, which restores homeostatic control through altered neuropeptidergic signaling.

AIM(S): This study aims to investigate the dynamics of neuropeptide expression in the hypothalamus following Dicer deletion and to assess whether neurogenesis contributes to the normalization of food intake and body weight.

METHOD(S): Using a Dicer CaMKCreERT2 mouse model, we induced Dicer deletion in the adult male and female mice. Mice were sacrificed at 3, 6, and 9 weeks post-induction to capture key phases of the obesity phenotype—onset, peak, and resolution. Hypothalamic tissue was collected for neuropeptidomic analysis. To assess cell proliferation, BrdU was administered systemically prior to tissue collection.

RESULTS: In accordance with prior observations, food intake and body weight reach a maximum around 5–6 weeks following mutation induction. This is followed by a spontaneous decline by weeks 8–9, with levels approaching those observed in control animals. Subsequent analyses will ascertain whether this phenotypic reversal is associated with particular neuropeptide alterations and elevated markers of neurogenesis.

CONCLUSIONS: The present study will provide insight into the molecular and cellular mechanisms underlying the transient obesity phenotype in Dicer-deficient mice. A comprehensive understanding of the role of neurogenesis and neuropeptide remodeling is essential for identifying novel therapeutic targets in the context of hypothalamic obesity.

FINANCIAL SUPPORT: OPUS