Circulating ghrelin is decreased in obesity, and peripheral ghrelin does not induce food intake in obese mice. We investigated whether ghrelin resistance was a centrally mediated phenomenon involving dysregulated neuropeptide Y (NPY) and agouti-related peptide (AgRP) circuits. We show that diet-induced obesity (DIO) (12 wk) suppresses the neuroendocrine ghrelin system by decreasing acylated and total plasma ghrelin, decreasing ghrelin and Goat mRNA in the stomach, and decreasing expression of hypothalamic GHSR. Peripheral (ip) or central (intracerebroventricular) ghrelin injection was able to induce food intake and arcuate nucleus Fos immunoreactivity in chow-fed but not high-fat diet-fed mice. DIO decreased expression of Npy and Agrp mRNA, and central ghrelin was unable to promote expression of these genes. Ghrelin did not induce AgRP or NPY secretion in hypothalamic explants from DIO mice. Injection of NPY intracerebroventricularly increased food intake in both chow-fed and high-fat diet-fed mice, indicating that downstream NPY/AgRP neural targets are intact and that defective NPY/AgRP function is a primary cause of ghrelin resistance. Ghrelin resistance in DIO is not confined to the NPY/AgRP neurons, because ghrelin did not stimulate growth hormone secretion in DIO mice. Collectively, our data suggests that DIO causes ghrelin resistance by reducing NPY/AgRP responsiveness to plasma ghrelin and suppressing the neuroendocrine ghrelin axis to limit further food intake. Ghrelin has a number of functions in the brain aside from appetite control, including cognitive function, mood regulation, and protecting against neurodegenerative diseases. Thus, central ghrelin resistance may potentiate obesity-related cognitive decline, and restoring ghrelin sensitivity may provide therapeutic outcomes for maintaining healthy aging.