1700-P: Sex- and Tissue-Specific Roles of X Chromosome Inactivation RNA (Xist) in Metabolic Homeostasis in Mice

Introduction and Objective: Xist, a long non-coding RNA essential for X chromosome inactivation (XCI) in female mammals, ensures dosage compensation of X-linked genes. Beyond XCI, Xist is implicated in immunity, cell proliferation, and obesity, a major risk factor for type 2 diabetes (T2D). This study explores Xist’s role in metabolism using mouse models. Methods: We developed mouse models with tissue-specific Xist knockouts using the Cre-loxP system. Xistlox/lox mice were crossed with tissue-specific Cre recombinase-expressing transgenic mice to generate Xist knockouts in adipocytes (XistadpKO), hepatocytes (XistalbKO), and pancreatic β-cells (XistinsKO) and compared with littermate control. Male (M) and female (F) mice were fed a Western diet (WD) from 6 weeks of age for 12 weeks and body weight was tracked weekly. Glucose tolerance (GTT) and insulin tolerance (ITT) were assessed. At the end of the experiment, animals were euthanized, and fat mass (subcutaneous and epididymal WAT) was measured. Results: F XistadpKO mice developed reduced weight gain and fat mass (subcutaneous and epididymal WAT) starting at 6 weeks compared to littermate controls, alongside improved GTT. These effects were not observed in M XistadpKO mice. M XistinsKO mice showed reduced weight gain, WAT mass and improved GTT, whereas F displayed modest improvements in these parameters. M XistalbKO mice exhibited increased weight gain but no significant GTT changes in either sex. Conclusion: These findings highlight the importance of Xist’s tissue- and sex-specific roles in metabolic homeostasis under diet-induced metabolic stress. Further molecular studies are necessary to elucidate its underlying mechanisms. Disclosure S. Haque: None. M. Qadir: None. W. Xu: None. J. Kharlyngdoh: None. F. Mauvais-Jarvis: None. Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (FMJ) (DK074970); NIH 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); NIH NIDDK (1K99DK140067)