We previously demonstrated that leptin has powerful central nervous system (CNS)‐mediated antidiabetic actions that are independent of the autonomic nervous system (ANS) and the pituitary. In this study, we examined if a circulating factor released by the brain contributes to leptin's chronic antidiabetic actions in insulin deficient rats. Male inbred 4‐week‐old Lewis rats (n=14) were conjoined by attaching their skin to allow shared circulation. Six weeks later, the rats were implanted with an intracerebroventricular (ICV) cannula into the lateral ventricle to infuse leptin in one rat and vehicle in the other rat of each pair. Eight days after surgery, food intake, body weight and blood glucose concentration were measured for 5 consecutive days and then streptozotocin (STZ) was injected (40 mg/kg) to induce insulin‐deficient diabetes in both rats. Five days after STZ injection, leptin (15 mg/day) or vehicle (0.5 ml/h) was delivered ICV continuously for 7 days via osmotic minipumps. STZ injection significantly increased average blood glucose concentration (359±19 vs. 79±6 mg/dL) and food intake (49±2 vs. 39±3 g/day). Despite higher food intake, average body weight decreased after STZ injection (619±23 vs. 664±23 g). Chronic ICV leptin infusion restored normoglycemia (110±31 vs. 359±19 mg/dL) in leptin‐treated rats and reduced blood glucose by ~27% in the paired parabiotic rat infused with vehicle (269±20 vs. 366±41 mg/dL). Leptin treatment did not reduce food intake (53±20 vs. 49±23 g/day) or body weight (619±23 vs. 610±20 g) in the paired rats. After stopping leptin treatment, blood glucose concentration returned to diabetic values in leptin‐treated (305±44 vs. 110±31 mg/dL) as well as in vehicle‐treated rats (330±11 vs. 269±20 mg/dL), and food intake increased 37% (67±5 vs. 49±3 g/day). These results suggest that the chronic antidiabetic effects of leptin may involve release into the systemic circulation of a brain‐derived neuroendocrine factor that enhances glucose homeostasis in insulin deficient rats. (NHLBI‐PO1HL51971, NIGMS P20GM104357)Support or Funding InformationDepartment of Physiology and Biophysics and Mississippi Center for Obesity Research. University of Mississippi Medical Center.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.