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ERα governs a specific gene expression program and metabolic function in white adipose tissue.

ABSTRACT: The White Adipose Tissue (WAT) has a major influence on energy metabolic functions and expresses the estrogen receptor ERα. Ovariectomized mice or mice carrying an ERα knock-out gene (ERKO), have a higher risk of becoming obese and developing metabolic disorders such as diabetes or dyslipidemia. To identify the direct target genes of ERα in visceral WAT, we treated ovariectomized mice with estradiol (E2) for 2 hours and proceeded to a genome-wide analysis of ERα binding sites to systemically identify them. We demonstrate that the E2/ERα pathway increases the expression of genes involved in the balance between lipids and glucose catabolism, the energy expenditure through the TCA cycle and the respiratory membrane chain. ERα binding sites and gene expression analysis in visceral and subcutaneous WAT, brown adipose tissue and liver show a specific program for each tissue. Our results are consistent with E2/ERα signaling protecting against metabolic diseases such as obesity by regulating an important gene regulatory network that helps maintaining normal metabolic functions in WAT.

ORGANISM(S): Mus musculus

PROVIDER: GSE121691 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Maternal obesity is linked with increased adverse outcomes for mother and fetus. However, the metabolic impact of excessive fat accumulation within the altered hormonal context of pregnancy is not well understood. We used a murine model of obesity, the high fat diet-fed C57BL/6J mouse to determine adipose tissue-mediated molecular mechanisms driving metabolic dysfunction throughout pregnancy. Remarkably, obese mice exhibited a normalization of visceral fat accumulation at late-stage pregnancy (-53%, P<0.001 E18.5) to achieve levels comparable in mass (per gram of body weight) to that of non pregnant, control diet fed mice. Moreover, whilst obese pregnant mice showed a marked glucose intolerance and apparent insulin resistance at mid-stage pregnancy (E14.5), glucose homeostasis converged with that of lean pregnant mice at late-stage pregnancy, suggesting an unexpected amelioration of the worsening metabolic dysfunction in obese pregnant mice. Transcriptomic analysis of the late-stage visceral fat indicated reduced de novo lipogenic drive (Me1, Fasn, Scd1, Dgat2), retinol metabolism (Rdh11, Rbp4) and inflammation (Mcp1, Tnfα) in obese pregnant mice that was confirmed functionally by their lower adipose proinflammatory macrophage density. Elevated expression of estrogen receptor a (ERα) in visceral adipose tissue was identified as potential unifying mechanism for the transcriptional changes and reduced adiposity of late stage obese pregnancy. Support for a role for ERα was provided by experiments showing that the ERα selective agonist PPT suppressed lipogenesis in primary mouse adipocytes and suppressed Me1, Fasn, SCD1 and Dgat2 mRNA levels in mature female human ChubS7 clonal fat cells. Our data reveal a novel role for elevated visceral adipocyte estrogen signaling as a protective mechanism against visceral fat hypertrophy and inflammation in late pregnancy. Pregnant high fat, pregnant control fat, non pregnant high fat, non pregnant control fat. Five biologial replictes each (20 samples).

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ERα governs a specific gene expression program and metabolic function in white adipose tissue.

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