Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring

Abstract

Exposure to inadequate nutritional conditions in critical windows of development has been associated to disturbances on metabolism and behavior in the offspring later in life. The role of the endocannabinoid system, a known regulator of energy expenditure and adaptive behaviors, in the modulation of these processes is unknown. In the present study, we investigated the impact of exposing rat dams to diet restriction (20% less calories than standard diet) during pre-gestational and gestational periods on: (a) neonatal outcomes; (b) endocannabinoid content in hypothalamus, hippocampus and olfactory bulb at birth; (c) metabolism-related parameters; and (d) behavior in adult male offspring. We found that calorie-restricted dams tended to have a reduced litter size, although the offspring showed normal weight at birth. Pups from calorie-restricted dams also exhibited a strong decrease in the levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), arachidonic acid (AA) and palmitoylethanolamide (PEA) in the hypothalamus at birth. Additionally, pups from diet-restricted dams displayed reduced levels of AEA in the hippocampus without significant differences in the olfactory bulb. Moreover, offspring exhibited increased weight gain, body weight and adiposity in adulthood as well as increased anxiety-related responses. We propose that endocannabinoid signaling is altered by a maternal caloric restriction implemented during the preconceptional and pregnancy periods, which might lead to modifications of the hypothalamic and hippocampal circuits, potentially contributing to the long-term effects found in the adult offspring.

Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor-Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators

“…The adult male offspring from calorie-restricted dams specifically exhibited an increased gene expression of the cannabinoid receptors Cnr1 and Cnr2 in the hypothalamus, and showed a decreased gene expression of the eCBs-metabolizing enzymes Napepld in liver, and Faah, Dagl α, Dagl β, and Mgll in PAT. These results likely indicate that the up-expression of the cannabinoid receptors in the hypothalamus at adulthood may result from a lower long-term cannabinoid activity that, in turn, could be produced by lower levels of eCBs and N-acylethanolamines (NAEs) in the hypothalamus of male offspring as was previous described at birth (Ramírez-López et al, 2016). This interpretation also agrees with the down-regulation of the endocannabinoid metabolism in peripheral tissues.…”

“…In contrast, a lower weight at birth has been described in several studies when the calorie-restricted diet was prolonged to birth (Desai et al, 2005; Lukaszewski et al, 2011). An explanation that emerges from these studies is that the putative fetal underweight caused by maternal undernutrition may be recovered in few days of normal nutrition, as was previously suggested (Cleal et al, 2007; Ramírez-López et al, 2016). Returning to our data, weight recovery in offspring may occur as a result of an accelerated catch-up growth before birth caused by an ad libitum maternal feeding.…”

“…Matias et al (2003) demonstrated a decrease in the hypothalamic levels of AEA (confirmed by Ramírez-López et al, 2016) and an absence of significant changes in the gene expression of Cnr1 and Faah in the hypothalamus of weaned pups after a maternal undernutrition throughout the last part of pregnancy and/or lactation. A possible explanation of this discrepancy could be related to the critical consequences of the maternal undernutrition at preconceptional periods.…”

“…Therefore, an alteration in the hypothalamic levels of endocannabinoids in newborn animals, as was previously described by Ramírez-López et al (2016), could impair the sympathetic neurotransmission and hormones involved in energy metabolism (Di Marzo et al, 2001; Keimpema et al, 2013, 2014; Cristino et al, 2014). Thus, the down-expression of the eCBs-degrading enzymes Faah and Mgll in the PAT of RC male offspring is consistent with an obese phenotype, hyperleptinemia, adiposity, and alterations in lipid metabolism in absence of increased food intake, as was previously described in animals with deficiency of FAAH and MAGL (Tourino et al, 2010; Geurts et al, 2015).…”

“…Regarding the potential relation between ECS and fetal undernutrition, a few studies have demonstrated that the maternal exposure to a calorie-restricted diet during pregnancy and/or lactation could decrease the hypothalamic endocannabinoids and/or acylethanolamines in offspring (Matias et al, 2003; Ramírez-López et al, 2016). However, it is unknown whether changes in nutritional programming by maternal diet restriction during fetal development could modify the expression of ECS components later in life and lead to long-lasting impact on energy metabolism and feeding behavior.…”