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Role of ghrelin and ghrelin o-acyltransferase in the maintenance of maternal glucose homeostasis in calorie-restricted mice

University of British Columbia

Ghrelin is a hormone that regulates energy homeostasis and is expressed in the stomach, hypothalamus and pituitary of humans and rodents. Ghrelin circulates as acylated (AG) and unacylated (UAG) ghrelin. Acylation is mediated by ghrelin O-acyltransferase (GOAT) and both forms of ghrelin are degraded by plasma proteases. Maintenance of euglycemia is important during pregnancy, where transplacental transfer of glucose is required for optimal fetal outcome. Maternal malnutrition is associated with decreased substrate availability and is a risk for hypoglycemia. AG prevents hypoglycemia in calorie-restricted (CR) mice by stimulating growth hormone (GH) release however its role in pregnancy remains unknown. I hypothesize that CR causes lower blood glucose in pregnant (P) compared to non-pregnant (NP) mice and that the GOAT-ghrelin axis is part of the response to this hypoglycemia. To determine ghrelin’s role in glucose homeostasis during pregnancy, wild-type (WT) and GOAT-KO (KO) mice were time-mated and fed-freely (FF) or CR by 50% for one week beginning at day 10.5 after conception. KO mice showed reduced fertility as conception was rare compared to WT animals. Unexpectedly, KO-CR mice also showed pregnancy termination early after CR was started and failed to survive to day 18 (=sacrifice), suggesting that AG plays a critical role in maintaining energy homeostasis during pregnancy. To further investigate the effect of ghrelin during pregnancy, several parameters of energy metabolism were analyzed: body composition, blood glucose, plasma AG, UAG, GH, GOAT/ghrelin expression, hepatic glycogen and PCK1 expression. I demonstrate that CR affects glucose metabolism more severely in WT-P and KO-NP mice (which cannot produce AG) compared to WT-NP mice. The additive effect of pregnancy and CR in GOAT-KO mice increases the severity of hypoglycemia. I propose that in WT animals, an increase in AG and UAG levels, whether due to increased production, decreased degradation, or both, serves to mitigate the decrease in blood glucose. The mechanisms of action of AG remain unclear but may involve stimulation of glycogenolysis and/or gluconeogenesis directly or indirectly (via stimulation of GH). My work supports a physiological role for the AG/UAG pathway in the regulation of blood glucose concentrations during pregnancy.

Text

2013-10-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/45334

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/