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.
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 receptorsCnr1andCnr2was increased in RC male hypothalamus, but a down-expression of most eCBs-metabolizing enzymes (Faah, Daglα, Daglβ, Mgll) and several key regulators of fatty-acid β-oxidation (Cpt1b, Acox1), mitochondrial respiration (Cox4i1), and lipid flux (Pparγ) 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 ofCnr1, Pparα,Pparγ, the eCBs-degrading enzymesFaahandMgll, thede novolipogenic enzymesAcacaandFasn, and the liver-specific cholesterol biosynthesis regulatorsInsig1andHmgcr. 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.
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de MadridMadrid, Spain; Hospital Universitario de GetafeMadrid, Spain.
authors.forename: María T
authors.initials: MT
authors.lastname: Ramírez-López
authors.affiliation: Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga Málaga, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Arco
authors.affiliation: Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Decara
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de MadridMadrid, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de MálagaMálaga, Spain.
authors.forename: Mariam
authors.initials: M
authors.lastname: Vázquez
authors.affiliation: Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga Málaga, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivera
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid Madrid, Spain.
authors.forename: Rosario Noemi
authors.initials: RN
authors.lastname: Blanco
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de MadridMadrid, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de MálagaMálaga, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Alén
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Gómez de Heras
authors.affiliation: Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de MálagaMálaga, Spain; Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Ciencias, Universidad de MálagaMálaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de MadridMadrid, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de MálagaMálaga, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
keywords: CB1 receptor; adipose tissue; hypothalamus; lipogenesis; lipoproteins; liver; maternal diet; β-oxidation