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Title: Abalation of Ghrelin receptor in leptin-deficient mice has paradoxical effects on glucose homeostasis compared to Ghrelin-abalated Leptin-deficient mice

Author
item LIN, YUEZHEN - Baylor College Of Medicine
item OSIFESO, IYABO - Children'S Nutrition Research Center (CNRC)
item MA, XIAOJUN - Baylor College Of Medicine
item MCGINNESS, OWEN - Vanderbilt University
item SMITH, ROY - Scripps Institute
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Endocrine Journal
Publication Type: Abstract Only
Publication Acceptance Date: 4/1/2010
Publication Date: 6/19/2010
Citation: Lin, Y., Osifeso, I., Ma, X., Mcginness, O., Smith, R., Sun, Y. 2010. Abalation of Ghrelin receptor in leptin-deficient mice has paradoxical effects on glucose homeostasis compared to Ghrelin-abalated Leptin-deficient mice [Abstract]. Endocrine Reviews. 31(03):P2-517.

Interpretive Summary:

Technical Abstract: Ghrelin is produced predominantly in stomach and is known to be the endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin is a GH stimulator and an orexigenic hormone. In contrast, leptin is an anorexic hormone, and leptin-deficient ob/ob mice are obese and diabetic. To study the functions of ghrelin in energy and glucose homeostasis, previously we generated ghrelin and leptin double knockout mice (Ghrelin-/-.ob/ob). We reported that the deletion of ghrelin in ob/ob mice had no effect on obesity, but significantly reduced glucose and increased insulin secretion compared to that of ob/ob mice. We further demonstrated that the increased insulin secretion was, in part, due to down-regulation of uncoupling protein 2 in pancreatic Beta cells. The deletion of GHSR in leptin-deficient mice would also have improved glucose homeostasis. In this study, GHSR and leptin double knockout mice (Ghsr-/-.ob/ob) were used. Glucose and insulin levels were monitored. Functional studies, GTT and ITT, were performed in mice at 10-14 weeks of age. Similar to Ghrelin-/-.ob/ob mice, deletion of Ghsr did not rescue the obese phenotype of ob/ob mice. Surprisingly, Ghsr-/-.ob/ob mice showed reduced insulin and worsened hyperglycemia when compared to that of ob/ob mice. In agreement, Ghsr-/-.ob/ob mice showed worsened glucose tolerance during a glucose tolerance test (GTT) and increased insulin resistance during an insulin tolerance test (ITT). Furthermore, we observed that similar to Ghsr-/-.ob/ob mice, Ghsr-/- mice showed reduced insulin secretion during a GTT and a hyperglycemic clamp. The glycemic phenotype of Ghsr-/-.ob/ob mice is in total contrast to that observed in Ghrelin-/-. ob/ob mice, implying ghelin's effect on glucose homeostasis in ob/ob mice may be independent of GHSR. The paradoxical effects of ghrelin and GHSR in leptin-deficient condition raise the possibility that there exists an as-yet-unknown additional ligand for GHSR, and/or an additional unknown ghrelin sub-type receptor, which are involved in glucose homeostatic regulation of ghrelin/GHSR signaling.