Neuronal XRN1 is required for maintenance of whole-body metabolic homeostasis

Control 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-specific Xrn1 conditional knockout mice (Xrn1-cKO) were generated, as Xrn1 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 of Xrn1-cKO mice. Therefore, we propose that XRN1 function in the hypothalamus is critical for maintenance of metabolic homeostasis. [Display omitted] •Forebrain specific Xrn1-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 the Xrn1-cKO hypothalamus Physiology; Molecular biology