A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner.

María Teresa Ramírez-López,Francisco Alén,Mariam Vázquez,Ermelinda Lomazzo,Juan Decara,Rosario Noemi Blanco,Clementine Hofmann,Rocío Arco,Raquel Gómez De Heras,Juan Suárez,Laura Bindila,Beat Lutz,Laura Orio,María Antón,Fernando Rodríguez De Fonseca

doi:10.1371/journal.pone.0174307

Abstract

Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid-related lipid signaling alterations might be involved in the long-term and sexual dimorphism effects commonly observed after undernutrition and low birth weight.

Highlights

Decades ago, Barker and colleagues demonstrated a strong and paradoxical correlation between low birth weight and the development of metabolic syndrome in adulthood [1]
Taking into account that the timing of caloric restriction could be critical on the effects exhibited by offspring [2, 18,19,20] and that these effects might be sex-dependent [11, 15,16,17], this study aims at investigating the impact of a moderate caloric restriction applied during the entire pregnancy on male and female newborn rats
Maternal diet restriction alters endocannabinoid levels in hypothalamus, hippocampus and olfactory bulb of offspring particular, it is interesting to note that these findings contrasts with the results recently described by our group in offspring from mothers exposed to the same caloric restriction during the preconceptional and gestational period, and with presumably decreased maternal stores

Summary

Introduction

Barker and colleagues demonstrated a strong and paradoxical correlation between low birth weight and the development of metabolic syndrome in adulthood [1]. Dutch Famine cohort studies showed the long-lasting and deleterious effects of undernutrition during early development [2] These investigations led to propose the DOHaD (Developmental origin of Health and Disease) hypothesis, stating that early life insults could lead to increased vulnerability to develop diseases later in life [1] through a process known as programming [3]. Despite the risk of metabolic diseases, underweight at birth has been associated to behavioral abnormalities, including alterations in cognitive performance, inadequate emotional responses or modifications in feeding behavior [8,9,10] This evidence emphasizes the importance to approach the burden of fetal undernutrition from different perspectives

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