Amylin acts acutely via the area postrema to reduce food intake and body weight but also interacts with leptin over longer periods of time, possibly via the ventromedial hypothalamus (VMH), to increase leptin signaling and phosphorylation of STAT3 (pSTAT3). We postulated that amylin enhances VMH leptin signaling by inducing IL-6 which then interacts with its gp130 receptor to activate STAT3 signaling and gene transcription downstream of the leptin receptor. We found that components of the amylin receptor (RAMPs1-3, CTR1a,b) are expressed in cultured VMH astrocytes, neurons and microglia, as well as in micropunches of arcuate and ventromedial hypothalamic (VMN) nuclei. Amylin exposure for 5 d increased IL-6 mRNA expression in VMH explants and microglia by 2-3 fold as well as protein abundance in culture supernatants by 5- and 2-fold. Amylin had no similar effects in cultured astrocytes or neurons. In rats, 5 d amylin treatment decreased body weight gain and/or food intake and increased ventromedial nucleus (VMN) IL-6 mRNA. Similar 5 d amylin treatment increased VMN leptin-induced pSTAT3 expression in wild type mice and rats infused with lateral ventricular IgG but not in IL-6 knockout mice or rats infused with ventricular IL-6 antibody. Lateral ventricular infusion of IL-6 antibody also prevented the amylin-induced decrease of body weight gain. These results show that amylin-induced VMH microglial IL-6 production is the likely mechanism by which amylin treatment interacts with VMH leptin signaling to increase its effect on weight loss.