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Title: Blunted hypothalamic ghrelin signaling reduces diet intake in rats fed a low-protein diet in late pregnancy

Author
item GAO, HAIJUN - Baylor College Of Medicine
item SISLEY, STEPHANIE - Children'S Nutrition Research Center (CNRC)
item YALLAMPALLI, CHANDRA - Baylor College Of Medicine

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/2015
Publication Date: 12/1/2015
Citation: Gao, H., Sisley, S., Yallampalli, C. 2015. Blunted hypothalamic ghrelin signaling reduces diet intake in rats fed a low-protein diet in late pregnancy. Physiological Reports. 3(12):e12629.

Interpretive Summary: The impact of protein intake in pregnancy on the health of mothers and their children is not known. Understanding this is crucial to determining optimal nutrition and intervention strategies for pregnant women with food scarcity or insecurity who often have protein-poor diets. We previously found that low-protein intake during pregnancy reduced overall food intake and body weight in late pregnancy in rats. In this study, we found that pregnant female rats fed a low-protein diet had a blunted response to ghrelin, an appetite stimulating hormone. Despite high ghrelin levels, the rats were not able to respond well to ghrelin given directly into their brain. Our research provides mechanistic evidence showing that low-protein diets interfere with ghrelin signaling in the brain, thus contributing to worsened body weight gain in the pregnant rat. This work is a first step toward understanding the role of protein in pregnancy on both the mother and child and can be used as a stepping stone for further mechanistic research in animals and translational research in humans.

Technical Abstract: Diet intake in pregnant rats fed a low-protein (LP) diet was significantly reduced during late pregnancy despite elevated plasma levels of ghrelin. In this study, we hypothesized that ghrelin signaling in the hypothalamus is blunted under a low-protein diet condition and therefore, it does not stimulate diet intake during late pregnancy. Female Sprague-Dawley rats were fed a normal (CT) or LP diet from Day 1 of pregnancy. On Day 21, 0.5 microg ghrelin was given into the third ventricle (ICV). Diet and water intake at 30, 60, and 120 min after ICV injection was measured. Hypothalami were dissected and analyzed for expression of genes related to appetite regulation ("Npy, Agrp, Pomc" and "Cart") and phosphorylation of AMP activated protein kinease(AMPK) and acetyl-CoA carboxylase(ACC) proteins (downstream proteins of ghrelin receptor activation). Results include: In response to ICV injection of ghrelin, (1) diet intake was significantly lower in LP compared to CT rats; (2) water intake was not affected in LP rats; (3) expression of "Npy" and "Agrp", but not "Pomc" and "Cart", were higher in the hypothalamus of LP compared to CT rats; (4) the abundance of phosphorylated AMPK and the ratio of phosphorylated to total AMPK, but not the abundance of total AMPK, were lower in LP compared to CT rats; (5) the abundance of phosphorylated ACC, but not total ACC, was lower in LP rats. These findings suggest that blunted ghrelin signaling in the hypothalamus of pregnant rats fed a LP diet leads to reduced diet intake and exacerbates gestational protein insufficiency.