AUTHOR=Ramírez-López María T. , Arco Rocío , Decara Juan , Vázquez Mariam , Rivera Patricia , Blanco Rosario Noemi , Alén Francisco , Gómez de Heras Raquel , Suárez Juan , Rodríguez de Fonseca Fernando 

TITLE=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

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=10

YEAR=2016

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2016.00241

DOI=10.3389/fnbeh.2016.00241

ISSN=1662-5153

ABSTRACT=<p>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 <italic>Cnr1</italic> and <italic>Cnr2</italic> was increased in RC male hypothalamus, but a down-expression of most eCBs-metabolizing enzymes (<italic>Faah, Dagl</italic>α<italic>, Dagl</italic>β<italic>, Mgll</italic>) and several key regulators of fatty-acid β-oxidation (<italic>Cpt1b, Acox1</italic>), mitochondrial respiration (<italic>Cox4i1</italic>), and lipid flux (<italic>Ppar</italic>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 <italic>Cnr1, Ppar</italic>α, <italic>Ppar</italic>γ, the eCBs-degrading enzymes <italic>Faah</italic> and <italic>Mgll</italic>, the <italic>de novo</italic> lipogenic enzymes <italic>Acaca</italic> and <italic>Fasn</italic>, and the liver-specific cholesterol biosynthesis regulators <italic>Insig1</italic> and <italic>Hmgcr</italic>. 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.</p>