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

Existe para su consulta material suplementario aportado por el editor.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.This work was supported by the Institutode Salud Carlos III, Ministerio de Economía y Competitividad (PI12/02261 and PI16/11698 to FRF, PI16/01374 and CP12/03109 to JS, and PSI-2012-35388 to RGH), Red de Trastornos Adictivos UE/ERDF (RD12/0028/0001 to FRF), CIBERobn, Consejerı´a de Economía, Innovación y Ciencia, Junta de Andalucía, UE/ERDF (PI45403, CTS-8221, CTS-433 to FRF), Consejería de Salud, Junta deAndalucía (SAS111224 to FRF), and the German Research Foundation DFG (FOR926, project CP1 to BL; CRC1080, subproject B08 to BL). MTRL has been funded by a FPU predoctoral fellowship of theSpanish Ministerio de Educacio´n, Cultura y Deporte (AP-2009-0225); JS holds “Miguel Servet”research contract from the National System ofHealth, ISCIII (grant numbers CP12/03109).Ye