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United States Department of Agriculture

Agricultural Research Service

Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF NUTRITIONAL METABOLISM DURING CHILDHOOD DEVELOPMENT

Location: Children's Nutrition Research Center

Title: 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
item Ma, Xiaojun -
item Lin, Yuezhen -
item Lin, Ligen -
item Qin, Guijun -
item Pereira, Fred -
item Haymond, Morey -
item Butte, Nancy -
item Sun, Yuxiang -

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 4, 2012
Publication Date: June 5, 2012
Citation: Ma, X., Lin, Y., Lin, L., Qin, G., Pereira, F.A., Haymond, M.W., Butte, N.F., Sun, Y. 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. American Journal of Physiology - Endocrinology and Metabolism. 303(3):E422-E431.

Interpretive Summary: Ghrelin is a hormone that can affect appetite and may have effects on insulin secretion, and thus may be important in type 2 diabetes. Mouse models are available in which either the animal's ability to make ghrelin (Ghrelin knockout) or to respond to ghrelin (GHS-R knockout) have been removed. When these animals are breed with leptin deficient mice (a mouse model of obesity and type 2 diabetes), we can detemine at least in mice the importance of this hormone and whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. In summary, we observed that the GHS-R-deficient leptin-deficient mice resulted in decreased insulin secretion and higher blood sugars. Thus, inhibition of the GHS-R may actually aggravate diabetes under certain conditions.

Technical 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 beta-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive beta-cell regulators (such as HIF-1 alpha, 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.

Last Modified: 4/20/2014
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