Simple SummaryATRXmutations occur in up to 17% of human pancreatic neuroendocrine tumours (PanNETs), and recent evidence points towards its inability to drive PanNET formation in mouse pancreas while predisposing individuals to inflammageing. Aiming to explore the additional non-tumourigenic consequences ofAtrxdeletion, we characterised an aged series ofAtrxconditional disruption in β cells using thePdx1promoter. Homozygous mice (P.AtrxHOM) exhibited obesity, diabetes, glucose intolerance, and pancreatic adiposity at a higher extent than age- and sex-matched controls (P.AtrxWT).AbstractAtrx loss was recently ascertained as insufficient to drive pancreatic neuroendocrine tumour (PanNET) formation in mice islets. We have identified a preponderant role of Atrx in the endocrine dysfunction in aRip-Cre;AtrxKOgenetically engineered mouse model (GEMM). To validate the impact of a differentCre-driver line, we used similar methodologies and characterised thePdx1-Cre;AtrxKO(P.AtrxKO) GEMM to search for PanNET formation and endocrine fitness disruption for a period of up to 24 months. Male and female mice presented different phenotypes. Compared toP.AtrxWT,P.AtrxHOMmales were heavier during the entire study period, hyperglycaemic between 3 and 12 mo., and glucose intolerant only from 6 mo.; in contrast,P.AtrxHOMfemales started exhibiting increased weight gains later (after 6 mo.), but diabetes or glucose intolerance was detected by 3 mo. Overall, all studied mice were overweight or obese from early ages, which challenged the histopathological evaluation of the pancreas and liver, especially after 12 mo. Noteworthily, losingAtrxpredisposed mice to an increase in intrapancreatic fatty infiltration (FI), peripancreatic fat deposition, and macrovesicular steatosis. As expected, no animal developed PanNETs. An obese diabetic GEMM of disruptedAtrxis presented as potentially useful for metabolic studies and as a putative candidate for inserting additional tumourigenic genetic events.