We demonstrate that in mice, reduced ghrelin — whether by germline genetic deletion of the gene encoding ghrelin, conditional ablation of ghrelin cells in adult mice, or physiological ablation as a result of diet-induced obesity — is associated with increases in mean islet size, percentage of very large islets, and β cell cross-sectional area. Here, GHRL is linked to obesity due to melanocortin 4 receptor deficiency.