1543-P: Feeding Regulatory Mechanism of Leptin Action in the Nucleus of the Solitary Tract and Area Postrema

Obesity is associated with brain leptin resistance. Leptin action in the hypothalamus activates STAT3 to lower feeding and weight, but whether extrahypothalamic regions such as the nucleus of the solitary tract (NTS) and area postrema (AP) mediate leptin action and resistance remain elusive. Here, we conducted refeeding and signaling studies to determine the impact of leptin infusion into the NTS or AP of male rats on chow or 3-day HF diet. Leptin vs vehicle infusion into the NTS (0.5μg; 0.2μL for 5min) increased STAT3 phosphorylation [lep: 1.7±0.1 vs. veh: 1.0±0.1 pSTAT3/total STAT3 intensity; p<0.01; n=6,6] and lowered food intake [lep: 77±5 vs. veh: 100±4 kCal; p<0.01; n=11,10] within 24h of refeeding in chow rats, while leptin infusion into the AP failed to lower feeding [lep: 93±6 vs. veh: 92±5 kCal; n=10,6]. When leptin was co-infused with STAT3 cell-permeable peptide (9.8ng dose that blocks the enzyme's phosphorylation) into the NTS, leptin failed to exert effects on STAT3 [lep + inhibitor: 0.9±0.1 vs. lep: 1.7±0.1 pSTAT3/total STAT3 intensity; p<0.01; n=5,6] and food intake [lep + inhibitor: 96±3 vs. lep: 77±5 kCal; p<0.05; n=13,11]. In 3d HF-induced hyperphagic [HF: 275±2 vs chow: 225±7 kCal; p<0.05; n=16,34] rats, NTS leptin vs vehicle failed to activate STAT3 [lep: 0.8±0.2 vs veh: 1±0.3 pSTAT3/total STAT3 intensity; n=5,5] or inhibit feeding [lep: 110±4 vs. veh: 113±3 kCal; n=10,6] in association with a reduction in leptin receptor expression in the NTS [HF: 0.68±0.02 vs. chow: 1±0.08; p<0.01; n=7,10]. In summary, we discover that 1) leptin administration into the NTS, but not the AP, lowers feeding and the NTS effect is depended on STAT3 activation, 2) 3d of HF feeding induces leptin resistance in the NTS to activate STAT3 and lower feeding in parallel to a reduction in leptin receptor expression. Thus, we unveil NTS as a site for leptin-STAT3 signaling to lower feeding and HF-induced leptin resistance. In contrast, AP appears do not sense leptin to regulate feeding.