Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications

Abstract

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates program obesity later in life. White adipose tissue (WAT) has been the focus of developmental programming events, although underlying mechanisms remain elusive. In rodents, WAT development primarily occurs during lactation. We previously reported that adult rat offspring from dams fed a high-fat (HF) diet exhibited fat accumulation and decreased peroxisome proliferator-activated receptor γ (PPARγ) mRNA levels in WAT. We hypothesized that PPARγ down-regulation occurs via epigenetic malprogramming which takes place during adipogenesis. We therefore examined epigenetic modifications in the PPARγ1 and PPARγ2 promoters in perirenal (pWAT) and inguinal fat pads of HF offspring at weaning (postnatal d 21) and in adulthood. Postnatal d 21 is a period characterized by active epigenomic remodeling in the PPARγ2 promoter (DNA hypermethylation and depletion in active histone modification H3ac and H3K4me3) in pWAT, consistent with increased DNA methyltransferase and DNA methylation activities. Adult HF offspring exhibited sustained hypermethylation and histone modification H3ac of the PPARγ2 promoter in both deposits, correlated with persistent decreased PPARγ2 mRNA levels. Consistent with the DOHaD hypothesis, retained epigenetic marks provide a mechanistic basis for the cellular memory linking maternal obesity to a predisposition for later adiposity.-Lecoutre, S., Pourpe, C., Butruille, L., Marousez, L., Laborie, C., Guinez, C., Lesage, J., Vieau, D., Eeckhoute, J., Gabory, A., Oger, F., Eberlé, D., Breton, C. Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.

Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress

“…Alterations in adipocyte differentiation and lipogenesis are associated with the development of metabolic disease and changes in PPAR expression are implicated in this pathogenic process [62,189]. Reduced PPARγ expression is observed in the adipose tissue of rodent offspring as a result of maternal undernutrition and a high-fat diet during pregnancy [71,112,113]. The observed reduction in PPARγ expression is dependent on sex, with only male offspring from a maternal high-fat diet being affected [112].…”

“…However, PPARγ and PPARα expression are upregulated in the adipose tissue of offspring in other studies of maternal undernutrition and high-fat diet, as well as in response to protein restriction or dexamethasone treatment during gestation [62,114,134]. Moreover, the expression of PPAR target genes, namely Srebp1, Fas, Lpl, hepatic lipase and stearoyl-CoA desaturase-1 (Scd1) are upregulated in the adipose of offspring exposed to maternal undernutrition, a high-fat diet or stress [84,[112][113][114]136]. Variations in offspring adipose Ppar expression between studies may relate to the timing and specific nutritional manipulation utilised, the fat depot studied, the age and sex of the offspring, whether birth weight was reduced and/or followed by catch-up growth, as well as whether obesity and insulin resistance also ensued in the model.…”

“…Pparβ, peroxisome proliferator activated receptor beta; Sirt1, sirtuin 1; Tnfα, tumour necrosis factor alpha; ↑/↓ promoter or Pparγ gene is observed in the liver and adipose, respectively [113,199]. In contrast, a reduction in Pparα promoter methylation is seen in the liver of offspring exposed to a maternal low-protein diet during gestation [195].…”

“…Decreased adiponectin and increased leptin expression in the offspring adipose tissue is associated with altered levels of acetyl H3K9 and dimethyl H3K9 at their gene promoters [220]. A reduction in Pparγ2 gene expression in the adipose of offspring born to obese dams is also associated with histone modifications; with adult offspring displaying a reduction in the active mark, H3AC, at the Pparγ2 promoter [113]. Histone modifications also occur in the adipose tissue of offspring born to dams fed a low-protein diet and given a high-fat diet postnatally.…”

“…Altered Pgc1α expression in the skeletal muscle of offspring exposed to protein restriction in utero is associated with the hypermethylation of its promoter [ 194 ]. Moreover, in offspring exposed to a maternal high-fat diet, hypermethylation of the Pparγ promoter or Pparγ gene is observed in the liver and adipose, respectively [ 113 , 199 ]. In contrast, a reduction in Pparα promoter methylation is seen in the liver of offspring exposed to a maternal low-protein diet during gestation [ 195 ] .…”