3107-LB: Novel Role for the Long Noncoding RNA XIST in Male Beta-Cell Autosomal Gene Regulation and Whole-Body Energy Homeostasis

Introduction and Objective: Sex differences in type 2 diabetes (T2D) susceptibility are well documented, but the mechanisms remain unclear. The long non-coding RNA XIST mediates X-chromosome inactivation in females and is thought absent in male somatic tissues; however, its cell-autonomous roles in male metabolism are unknown. We investigated Xist function in mouse pancreatic β-cells. Methods: We generated β-cell-specific Xist knockout (βXistKO) mice by crossing loxP-flanked Xist (exons 2-7) mice with Ins1-Cre transgenics. Deletion was confirmed by reduced Xist expression in isolated islets. Male and female mice were weaned onto a Western diet (WD), and body weight and glucose homeostasis were monitored longitudinally. Bulk RNA-seq was performed on isolated islets. Results: Female βXistKO mice showed no changes in β-cell function or glucose homeostasis through 18 weeks. In contrast, male βXistKO mice exhibited reduced body weight and fat mass with improved glucose tolerance. Islet transcriptomics revealed a distinct male β-cell phenotype: canonical β-cell genes were preserved, while stress genes including Npy and Btg2 were induced. Marked Npy upregulation, normally expressed during β-cell development and in neurons, suggested cellular stress or neuronal-like reprogramming. Pathway analysis showed enrichment of genes involved in vesicle function (Snap25, Syt1, Cplx1), neuronal structure (Tubb3), cholinergic vesicular transport (Slc18a3), and neuropeptide signaling (Npy, Pdyn), consistent with enhanced islet innervation or neuron-like gene expression. Upregulation of the T2D GWAS gene C2cd4b suggests Xist loss elicits a β-cell response conferring protection against WD-induced metabolic decline. Conclusion: We identify a novel male-specific role for Xist in β-cells, regulating autosomal gene expression independently of X-chromosome inactivation and influencing β-cell stress responses, islet neurobiology, and whole-body energy and glucose homeostasis. Disclosure S. Haque: None. M. Qadir: None. W. Xu: None. F. Mauvais-Jarvis: None. Funding NIH National Instituteof Diabetes andDigestive and KidneyDiseases (FMJ) (DK074970NIH), National Institute of General Medical Sciences (FMJ) (P20GM152305), U.S. Department of Veterans Affairs Merit Award (FMJ)(BX005812), NIH National Institute of Diabetes and Digestive and Kidney Diseases (IIDP) (2UC4DK098085)