Loss of leptin receptor-expressing cells in the hindbrain decreases forebrain leptin sensitivity

Previous studies indicate that inhibition of food intake by leptin is mediated by an integrated response to activation of hypothalamic and hindbrain receptors. This study tested whether loss of hindbrain leptin receptor signaling changed sensitivity to forebrain leptin. Injections of leptin-conjugated saporin (Lep-Sap) into the medial nucleus of the solitary tract (NTS) were used to destroy hindbrain leptin receptor-expressing neurons of male Sprague-Dawley rats. Controls were injected with saporin conjugated with a nonsense peptide (Blk-Sap). Lep-Sap had no effect on daily food intake or body weight, but expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in the NTS following a peripheral injection of leptin was abolished 26 days after Lep-Sap injections. To test forebrain leptin sensitivity. Lep-Sap and Blk-Sap rats received third-ventricle injections of 0, 0.05, 0.1. 0.25. or 0.5 mu g leptin. Food intake was inhibited by 0.25 and 0.5 mu g leptin in Bik-Sap rats, but there was no significant effect of leptin on food intake of Lep-Sap rats. There was no difference in hypothalamic pSTAT3 in unstimulated conditions, but pSTAT3 was lower in the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH) of Lep-Sap rats compared with Blk-Sap rats following a third-ventricle injection of 0.25 mu g leptin. These results are consistent with previous data showing that loss of VMH leptin receptor-expressing cells prevents weight loss caused by fourth-ventricle leptin infusion and show that the integrated response between the hindbrain and forebrain is heavily dependent on leptin activity in the VMH.