Maternal hypercaloric diet affects factors involved in lipid metabolism and the endogenous cannabinoid systems in the hypothalamus of adult offspring: sex-specific response of astrocytes to palmitic acid and anandamide

ABSTRACT

Aim: We aimed to investigate whether maternal malnutrition during gestation/lactation induces long-lasting changes on inflammation, lipid metabolism and endocannabinoid signaling in the adult offspring hypothalamus and the role of hypothalamic astrocytes in these changes.

Methods: We analyzed the effects of a free-choice hypercaloric palatable diet (P) during (pre)gestation, lactation and/or post-weaning on inflammation, lipid metabolism and endogenous cannabinoid signaling in the adult offspring hypothalamus. We also evaluated the response of primary hypothalamic astrocytes to palmitic acid and anandamide.

Results: Postnatal exposure to a P diet induced factors involved in hypothalamic inflammation (Tnfa and Il6) and gliosis (Gfap, vimentin and Iba1) in adult offspring, being more significant in females. In contrast, maternal P diet reduced factors involved in astrogliosis (vimentin), fatty acid oxidation (Cpt1a) and monounsaturated fatty acid synthesis (Scd1). These changes were accompanied by an increase in the expression of the genes for the cannabinoid receptor (Cnr1) and Nape-pld, an enzyme involved in endocannabinoid synthesis, in females and a decrease in the endocannabinoid degradation enzyme Faah in males. These changes suggest that the maternal P diet results in sex-specific alterations in hypothalamic endocannabinoid signaling and lipid metabolism. This hypothesis was tested in hypothalamic astrocyte cultures, where palmitic acid (PA) and the polyunsaturated fatty acid N-arachidonoylethanolamine (anandamide or AEA) were found to induce similar changes in the endocannabinoid system (ECS) and lipid metabolism.

Conclusion: These results stress the importance of both maternal diet and sex in long term metabolic programming and suggest a possible role of hypothalamic astrocytes in this process.

KEYWORDS:

• Astrocytes
• endocannabinoid system
• hypothalamus
• maternal diet
• perinatal programing
• perinatal diet
• lipid metabolism
• inflammation

Data availability statement

The data that support the findings of this study are available on reasonable request from the corresponding author.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Instituto de Salud Carlos III: [Grant Number PI16/01374, PI16/00485, PI16/01698, CPII17/00024, CD19/00068, CP19/00068, PI16/01374, PI19/00343, PI19/00166]; CIBEROBN and Ministerio de Economía y Competitividad: [Grant Number BFU2017-82565-C2-1-R].

Notes on contributors

Patricia Rivera

Patricia Rivera is a Postdoctoral Researcher in the Neuropsychopharmacology group of the IBIMA Institute. The group has a extensive experience in the development of new drugs for the treatment of disorders related to motivational behavior, especially in obesity and drugs of abuse areas.

Santiago Guerra-Cantera

Santiago Guerra-Cantera is a Ph.D. student in the Department of Endocrinology at Hospital Infantil Universitario Niño Jesús.

Antonio Vargas

Antonio Vargas is laboratory technician in the Neuropsychopharmacology group of the IBIMA Institute.

Francisca Díaz

Francisca Díaz is a postdoctoral Researcher in the Department of Endocrinology at Hospital Infantil Universitario Niño Jesús.

Rocío García-Úbeda

Rocío García-Úbeda is a postdoctoral Researcher in the Department of Endocrinology at Hospital Infantil Universitario Niño Jesús.

Rubén Tovar

Rubén Tovar is a Ph.D. student in the Neuropsychopharmacology group of the IBIMA Institute.

María Teresa Ramírez-López

María Teresa Ramírez-López is a postdoctoral Researcher in the Universitary Hospital of Getafe.

Jesús Argente

Jesús Argente (M.D., Ph.D) is Full Professor of Pediatrics at Universidad Autónoma of Madrid and Chief of Pediatrics and of Pediatric Endocrinology at Hospital Infantil Universitario Niño Jesús. His research includes the endocrinology of pathological growth, puberty and metabolism.

Fernando Rodríguez de Fonseca

Fernando Rodríguez de Fonseca led Neuropsychopharmacology group of the IBIMA Institute.

Juan Suárez

Juan Suárez is a Postdoctoral Researcher in the Neuropsychopharmacology group of the IBIMA Institute.

Julie A. Chowen

Julie A. Chowen (Ph.D.) is Senior Researcher in the Department of Endocrinology at Hospital Infantil Universitario Niño Jesús. Her research is focused on the neuroendocrine control of energy balance with a special interest in the role of astrocytes in this process.