Furthermore, while the present findings confirm that meal- and obesity-associated plasma ghrelin reductions require ghrelin cell–expressed IRs, future studies could help determine the mechanisms responsible for the rises in plasma ghrelin observed in GhIRKO mice 2 hours after the reintroduction of food following a 24-hour fast (Figure 5A), 30 minutes after starting the hyperinsulinemic-hypoglycemic clamp procedure (Figure 2A), 120 minutes after starting the hyperinsulinemic-euglycemic clamp procedure (Figure 3, A and E), or after chronic exposure to high-fat diet (Figure 6B). This evidence concerns the gene GHRL and obesity due to melanocortin 4 receptor deficiency.