This presentation will summarize recent findings in respect to amylin’s role in satiation, as an adiposity signal and beyond. Numerous lines of evidence indicate that amylin contributes to meal-ending satiation. This action seems to be mediated by direct action of amylin on area postrema (AP) neurons. Our recent data showed that noradrenergic neurons in the AP appear to be essential for amylin’s effect on eating. Amylin’s ability to induce c-Fos expression and to reduce eating seems to be nutrient dependent. Amylin increased c-Fos expression in the AP more in fasted rats and in rats fed a nutrient-deficient non-caloric diet (NCD) than in rats fed chow ad libitum. Supplementation of NCD with protein, but not with glucose or fat, reduced the amylin-mediated AP c-Fos response. Similarly, parenteral injection of an amino acid mixture also significantly attenuated the amylin-induced c-Fos expression in the AP. Feeding studies are in line with these findings in that amylin injection failed to reduce food intake in NCD/protein fed rats, whereas amylin did reduce food intake in animals fed NCD, NCD/glucose or NCD/fat. Amylin’s effect to reduce eating was particularly strong in rats fed a low-protein diet. The exact mechanisms through which protein diets/amino acids reduce amylin’s effect to inhibit eating are still unknown. Interestingly, amylin seems not only to activate hindbrain neurons, specifically neurons projecting from the AP to the nucleus of the solitary tract (NTS), but amylin may also act as a trophic factor in the central nervous system, because amylin-deficient mice have a significantly reduced fibre density in AP to NTS projections. Retrograde and anterograde tracing studies using cholera toxin subunit b and biotinylated dextran amine, respectively, together with previous c-Fos studies performed in adult rats indicate that amylin activates a specific neural circuit from the AP via the NTS and the lateral parabrachial nucleus to more rostral brain areas. Next to its involvement in meal ending satiation, amylin also shares typical features of adiposity signals. E.g., its basal plasma levels correlate with the amount of body adiposity. We recently investigated central amylin’s effects on body weight (bw) gain in rats. Four groups of rats were included in this experiment, all equipped with 3rd ventricular cannula that were implanted under anaeshthesia. Two groups were fasted for 48h, two other groups were fed ad libitum. One group of each received a 14 day chronic intra-3rd ventricle infusion of amylin, controls received saline. The fasted rats lost about 40g in two days. After refeeding, the saline infused controls regained bw quickly and reached the same level as ad libitum fed rats. Interestingly, both groups of amylin-infused rats eventually reached the same level of bw that was significantly lower than in saline treated rats. This indicates that central levels of amylin influence the bw to be maintained. In a similar experiment, half of the rats were overfed for 3 weeks with Ensure to increase their bw by about 60g above that of chow-fed rats. Then, minipumps were implanted and all rats received chow only. Surprisingly, amylin infused rats that had been overfed before seemed to demonstrate amylin insensitivity because their body weight did not decrease below that of saline controls. Consistent with the idea that amylin may also act as an adiposity signal similar to leptin or insulin, amylin has also been shown to influence energy expenditure (EE). This means that amylin-infused animals maintain EE at a level similar to controls, despite lower food intake and bw gain. This suggests that amylin may prevent the compensatory decrease of EE due to reduced food intake. Of high clinical relevance are the findings that combinations of amylin and leptin reduce eating more than the individual treatments alone. This has been shown by us after acute administration, and several other chronic infusion studies also demonstrate the long term benefit of combining amylin and leptin to produce strong body weight lowering effects. In fact, amylin seems to reduce leptin resistance that is typically associated with obesity. The underlying mechanism may involve increased leptin receptor expression in the hypothalamus in general, and improved leptin signaling in the ventromedial hypothalamus in particular. To summarize, amylin produces meal ending satiation via the AP. We propose that amylin also influences brain hardware in a way that in principle is comparable to effects of leptin in the hypothalamus. Studies designed to understand the influence of dietary components on the effectiveness of amylin to reduce eating should be explored further. Finally, the therapeutic potential of simultaneous manipulations of amylin and leptin signalling is of high clinical relevance and deserves further attention.