摘要：SummaryControl of mRNA stability and degradation is essential for appropriate gene expression, and its dysregulation causes various disorders, including cancer, neurodegenerative diseases, diabetes, and obesity. The 5′–3′ exoribonuclease XRN1 executes the last step of RNA decay, but its physiological impact is not well understood. To address this, forebrain-specificXrn1conditional knockout mice (Xrn1-cKO) were generated, asXrn1 null mice were embryonic lethal.Xrn1-cKO mice exhibited obesity with leptin resistance, hyperglycemia, hyperphagia, and decreased energy expenditure. Obesity resulted from dysregulated communication between the central nervous system and peripheral tissues. Moreover, expression of mRNAs encoding proteins that regulate appetite and energy expenditure was dysregulated in the hypothalamus ofXrn1-cKO mice. Therefore, we propose that XRN1 function in the hypothalamus is critical for maintenance of metabolic homeostasis.Graphical abstractDisplay OmittedHighlights•Forebrain specificXrn1-cKO mice exhibit obesity with hyperphagia•Xrn1-cKO mice exhibit leptin resistance, insulin resistance, and impaired glucose tolerance•Xrn1-cKO mice cannot utilize fat as an energy source and mainly use carbohydrate•AgRP expression is upregulated in theXrn1-cKO hypothalamusPhysiology; Molecular biology
