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

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.

Differential Effects of Post-Weaning Diet and Maternal Obesity on Mouse Liver and Brain Metabolomes

“…These variations may affect the production of DHA, an essential long-chain polyunsaturated fatty acid (PUFA) of the n-3 series, involved in both membrane fluidity and neuroprotective/inflammatory processes in the brain [65,66]. This is consistent with results showing that obesity alters the serum long-chain PUFA profile [67], that moderate gestational dietary restriction alters their levels in the HYP, hippocampus and WOB of newborns [68] and that n-3 PUFA deficiency is associated with a decrease in olfactory performance [69].…”

Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing

“…Interestingly, a high and increasing amount of PEA has recently been found in milk samples from mothers belonging to underserved populations, where milk represents a food of primary importance to avoid infant malnutrition [31]. Accordingly, deregulated levels of PEA in breast milk were repeatedly found to negatively affect the growth of offspring [32,33]. One might thus speculate that PEA represents an early nutrient.…”

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

“…Similar to the NHP model used in this study, offspring of the MNR group displayed a reduced weight gain and lower body weight (Ramirez‐Lopez et al. ). While our study did not demonstrate changes in the enzymes involved in the synthesis/degradation of ECs in opposite to a rodent model, where AA and 2‐AG levels were decreased in the hypothalamus of male and female offspring, respectively, demonstrating fetal sex‐specific effect of MNR.…”

“…Importantly, in relation to the present study, fetal ECS is modified by changes in maternal nutritional status (Ramirez‐Lopez et al. , ) and pharmacological targeting of the ECS has great potential for treatment of schizophrenia (disorder, programmed by maternal folic acid deficiency (Canever et al. )), autism spectrum disorder and epilepsy (Di Marzo ).…”

“…However, data on the effects of MNR on the endogenous cannabinoid system (ECS) are sparse and limited to hypothalamus, hippocampus, liver, and perirenal fat in rodent model (Ramirez‐Lopez et al. ,, ).…”