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

Abstract

Maternal malnutrition causes long-lasting alterations in feeding behavior and energy homeostasis in offspring. It is still unknown whether both, the endocannabinoid (eCB) machinery and the lipid metabolism are implicated in long-term adaptive responses to fetal reprogramming caused by maternal undernutrition. We investigated the long-term effects of maternal exposure to a 20% standard diet restriction during preconceptional and gestational periods on the metabolically-relevant tissues hypothalamus, liver, and perirenal fat (PAT) of male and female offspring at adulthood. The adult male offspring from calorie-restricted dams (RC males) exhibited a differential response to the CB1 antagonist AM251 in a chocolate preference test as well as increased body weight, perirenal adiposity, and plasma levels of triglycerides, LDL, VLDL, bilirubin, and leptin. The gene expression of the cannabinoid receptors <i>Cnr1</i> and <i>Cnr2</i> was increased in RC male hypothalamus, but a down-expression of most eCBs-metabolizing enzymes (<i>Faah, Dagl</i>α<i>, Dagl</i>β<i>, Mgll</i>) and several key regulators of fatty-acid β-oxidation (<i>Cpt1b, Acox1</i>), mitochondrial respiration (<i>Cox4i1</i>), and lipid flux (<i>Ppar</i>γ) was found in their PAT. The female offspring from calorie-restricted dams exhibited higher plasma levels of LDL and glucose as well as a reduction in chocolate and caloric intake at post-weaning periods in the feeding tests. Their liver showed a decreased gene expression of <i>Cnr1, Ppar</i>α, <i>Ppar</i>γ, the eCBs-degrading enzymes <i>Faah</i> and <i>Mgll</i>, the <i>de novo</i> lipogenic enzymes <i>Acaca</i> and <i>Fasn</i>, and the liver-specific cholesterol biosynthesis regulators <i>Insig1</i> and <i>Hmgcr</i>. Our results suggest that the long-lasting adaptive responses to maternal caloric restriction affected cannabinoid-regulated mechanisms involved in feeding behavior, adipose β-oxidation, and hepatic lipid and cholesterol biosynthesis in a sex-dependent manner.