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Publication
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.
Authors Ma X, Lin Y, Lin L, Qin G, Pereira FA, Haymond MW, Butte NF, Sun Y
Submitted By Yuxiang Sun on 10/11/2012
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2012
Date Published 8/1/2012
Volume : Pages 303 : E422 - E431
PubMed Reference 22669248
Abstract 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 ß-cell regulators (such as
UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive ß-cell regulators
(such as HIF-1a, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr
ablation impairs pancreatic ß-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.




Strains




Genes
SymbolDescription
Ghsrgrowth hormone secretagogue receptor
Ghrlghrelin

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