| First Author | Ma X | Year | 2012 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 303 |
| Issue | 3 | Pages | E422-31 |
| PubMed ID | 22669248 | Mgi Jnum | J:187287 |
| Mgi Id | MGI:5436159 | Doi | 10.1152/ajpendo.00576.2011 |
| Citation | Ma X, et al. (2012) Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice. Am J Physiol Endocrinol Metab 303(3):E422-31 |
| abstractText | The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ob mice (Ghsr(-/-):ob/ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ob mice upregulated negative beta-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive beta-cell regulators (such as HIF-1alpha, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic beta-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ob mice did not affect the islet size; the average islet size of Ghsr(-/-):ob/ob mice is similar to that of ob/ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway. |
