Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice

Abstract

Key pointsr Maternal obesity reduces adipogenic progenitor density in offspring adipose tissue. r The ability of adipose tissue expansion in the offspring of obese mothers is limited and is associated with metabolic dysfunction of adipose tissue when challenged with a high-fat diet.r Maternal obesity induces DNA demethylation in the promoter of zinc finger protein 423, which renders progenitor cells with a high adipogenic capacity.r Maternal obesity demonstrates long-term effects on the adipogenic capacity of progenitor cells in offspring adipose tissue, demonstrating a developmental programming effect.Abstract Maternal obesity (MO) programs offspring obesity and metabolic disorders, although the underlying mechanisms remain poorly defined. Progenitor cells are the source of new adipocytes. The present study aimed to test whether MO epigenetically predisposes adipocyte progenitors in the fat of offspring to adipogenic differentiation and subsequent depletion, which leads to a failure of adipose tissue plasticity under positive energy balance, contributing to adipose tissue metabolic dysfunction. C57BL/6 female mice were fed either a control diet (10% energy from fat) or a high-fat diet (45% energy from fat) for 8 weeks before mating. Male offspring of control (Con) and obese (OB) dams were weaned onto a regular (Reg) or obesogenic (Obe) diet until 3 months of age. At weaning, male OB offspring had a higher expression of Zinc finger protein 423 (zfp423), a key transcription factor in adipogenesis, as well as lower DNA methylation of its promoter in progenitors of epididymal fat compared to Con offspring, which was correlated with enhanced adipogenic differentiation. At 3 months of age, progenitor density was 30.9 ± 9.7% lower in OB/Obe compared to Con/Obe mice, accompanied by a limited expansion of the adipocyte number when challenged with a high-energy diet. This difference was associated with lower DNA methylation in the zfp423 promoter in the epididymal fat of OB/Obe offspring, which was correlated with greater macrophage chemotactic protein-1 and hypoxia-inducible factor 1α expression. In summary, MO epigenetically limits the expansion capacity of offspring adipose tissue, providing an explanation for the adipose metabolic dysfunction of male offspring in the setting of MO. Abbreviations aP2, adipocyte protein 2; EpiWAT, epididymal white adipose tissue; H&E, haemotoxylin and eosin; IL-6, interleukin-6; IngWAT, inguinal white adipose tissue; MCP, macrophage chemotactic protein; MO, maternal obesity; PDGFRα, plate-derived growth factor receptor α; Pref1, preadipocyte factor 1; PPARγ, peroxisome proliferator-activated receptor γ; SVFs, stromal-vascular fractions; TNF, tumor necrosis factor; zfp423, zinc finger protein 423.

Thy1 (CD90) expression is regulated by DNA methylation during adipogenesis

“…Increased Thy1 methylation levels may be inherited by offspring from obese parents. Interestingly, animal models of obesity have shown that maternal obesity epigenetically alters visceral fat progenitor cells in male offspring making them more prone to form adipocytes (49). Although Thy1 expression was not measured in those studies, it may be that Thy1 is lower in the more adipogenic progenitor cells.…”

Dietary apple polyphenols promote fat browning in high‐fat diet‐induced obese mice through activation of adenosine monophosphate‐activated protein kinase α

“…The different fat depots have different densities of progenitor cells. Subcutaneous fat possesses a higher density of progenitor cells and a higher expansion capacity than that of visceral fat, which may be more sensitive to pharmacological or nutritional stimuli . The low density of PDGFR α ‐positive progenitor cells in EpiWAT limits de novo formation of beige adipocytes, which might explain the lack of changes in EpiWAT beige adipogenesis of APs‐treated mice.…”

Raspberry Supplementation Improves Insulin Signaling and Promotes Brown‐Like Adipocyte Development in White Adipose Tissue of Obese Mice

“…cDNA was synthesized using iScript cDNA Synthesis Kit (Bio‐Rad, Hercules, CA). qPCRs were performed on a CFX96 RT‐PCR system (Bio‐Rad) . 18s was used as the reference gene.…”