Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner

Simon Lecoutre (1) , Frederik Oger (1) , Charlène Pourpe (1) , Laura Butruille (1) , Lucie Marousez (1) , Anne Dickes-Coopman (1) , Christine Laborie (1) , Céline Guinez (1) , Jean Lesage (1) , Didier Vieau (1) , Claudine Junien (2, 3, 4) , Delphine Eberlé (1) , Anne Gabory (2, 3) , Jérôme Eeckhoute (5, 6, 7) , Christophe Breton (1)

1 EPS - Environnement périnatal et croissance - EA 4489
2 BDR - Biologie du Développement et Reproduction
3 Université Paris-Saclay
4 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
5 RNMCD - Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011
6 Université de Lille
7 CHU de Lille - Centre Hospitalier Universitaire de Lille

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner. We hypothesized that leptin upregulation occurs via epigenetic malprogramming, which takes place early during development of WAT. As a first step, we identified in silico two potential enhancers located upstream and downstream of the leptin transcription start site that exhibit strong dynamic epigenomic remodeling during adipocyte differentiation. We then focused on epigenetic modifications (methylation, hydroxymethylation, and histone modifications) of the promoter and the two potential enhancers regulating leptin gene expression in perirenal (pWAT) and inguinal (iWAT) fat pads of HF offspring during lactation (postnatal days 12 (PND12) and 21 (PND21)) and in adulthood. PND12 is an active period for epigenomic remodeling in both deposits especially in the upstream enhancer, consistent with leptin gene induction during adipogenesis. Unlike iWAT, some of these epigenetic marks were still observable in pWAT of weaned HF offspring. Retained marks were only visible in pWAT of 9-month-old HF rats that showed a persistent "expandable" phenotype. Consistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions especially within intergenic sequences, linked to higher leptin gene expression in adult HF offspring in a depot-specific manner.

Mots clés: Developmental origin of health and disease; Epigenetic mechanisms; Fat expansion; Perinatal programming; adipose tissue; gene expression; obesity; immunoprecipitation reaction; chromatin

Mots clés: tissu adipeux; leptine; expression génique; obésité; épigénétique; immunoprécipitation; modification épigénique; chromatine

Domaines: Biologie du développement

Simon Lecoutre, Frederik Oger, Charlène Pourpe, Laura Butruille, Lucie Marousez, et al.. Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner. Molecular metabolism, 2017, 6 (8), pp.922-930. ⟨10.1016/j.molmet.2017.05.010⟩. ⟨hal-01607373⟩