Maternal immune activation disrupts maternal and offspring lipid signalling in association with reduced PPARα-FGF21 expression

Maternal immune activation (MIA) during gestation increases neurodevelopmental disorder risk, but its metabolic mechanisms remain unclear. Given the role of lipid metabolism in fetal brain development and endocannabinoid signaling, we investigated whether MIA is associated with alteration in maternal and offspring lipid pathways and peroxisome proliferator-activated receptor α (PPARα)-related signaling. Pregnant rats received a single i.v. injection of the viral mimetic polyinosinic: polycytidylic acid [poly (I: C)] at gestational day 15.

Lipidomic and gene-expression analyses were conducted in maternal, fetal, and adolescent male and female offspring tissues to assess fatty acid composition, desaturase activity, de novo lipogenesis (DNL), and N-acylethanolamines (NAE) signaling. MIA induced maternal weight loss, and was associated with lower hepatic DNL and Δ5/Δ6-desaturase activities, and decreased Fasn, Pparα, and Fgf21 expression, suggesting alterated PPARα-FGF21 signaling. These alterations were accompanied by reduced hepatic total NAE, including N-oleoylethanolamine (OEA), N-palmitoleoylethanolamine (POEA) and N-docosahexaenoylethanolamine (DHAEA), and hippocampal DHAEA.

Fetal tissues showed diminished DHAEA and DNL indices. In adolescence, males displayed cortical decreases in NAE and 2-arachidonoyl-glycerol (2-AG), whereas females exhibited hepatic lipid accumulation but preserved cortical lipid signaling. These findings suggest that altered PPARα-related lipid signaling may contribute to the association between prenatal inflammation and metabolic alterations.

Future studies should determine whether targeted nutritional activation of PPARα could mitigate MIA-induced alterations. This work was supported by: Progetti di Rilevante Interesse Nazionale (Grant Nos. PRIN 2022 P20229CCLB and 2022NSLB3Z [to MP]) from the Italian Ministry of University and Research, by the Assessorato alla Programmazione (Grant No.

PNRR-MAD-2022-12375802; Regione Autonoma della Sardegna) [to MP]), and by Hybrid Hub: Modelli cellulari e COMputazionali, micro e nanotEcnologie per la personalizzazione di Terapie innovAtive grant (Grant No. T4-AN-10 [to MP]) from the Italian Ministry of Health. These authors contributed equally: Elisabetta Murru and Michele Santoni.

These authors jointly supervised this work: Sebastiano Banni and Marco Pistis. Department of Biomedical Sciences, University of Cagliari, Monserrato, Cagliari, 09042, Italy Elisabetta Murru, Michele Santoni, Claudia Manca, Gianfranca Carta, Monica Cabboi, Andrea Mastio, Sebastiano Banni & Marco Pistis Neuroscience Institute, Section of Cagliari, National Research Council of Italy (CNR), Cagliari, Italy Unit of Clinical Pharmacology, University Hospital, Cagliari, Italy The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.