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. Academic Article uri icon


  • 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 -cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive -cell regulators (such as HIF-1, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic -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.

published proceedings

  • Am J Physiol Endocrinol Metab

altmetric score

  • 0.25

author list (cited authors)

  • Ma, X., Lin, Y., Lin, L., Qin, G., Pereira, F. A., Haymond, M. W., Butte, N. F., & Sun, Y.

citation count

  • 32

complete list of authors

  • Ma, Xiaojun||Lin, Yuezhen||Lin, Ligen||Qin, Guijun||Pereira, Fred A||Haymond, Morey W||Butte, Nancy F||Sun, Yuxiang

publication date

  • August 2012