Estradiol cycling drives female obesogenic adipocyte hyperplasia

• Published in: Cell reports (Cambridge) Vol. 42; no. 4; p. 112390
• Main Authors: Saavedra-Peña, Rocío del M., Taylor, Natalia, Flannery, Clare, Rodeheffer, Matthew S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2023; Elsevier
• Subjects: adipocyte precursors; Adipocytes - pathology; Adipogenesis; Adipose Tissue, White; Animals; CP: Metabolism; Diet, High-Fat - adverse effects; estradiol; Estradiol - pharmacology; Estrogen Receptor alpha; estrogen signaling; Estrogens; estrous cycle; Female; female obesity; high-fat diet; Hyperplasia - pathology; Male; Mice; Mice, Inbred C57BL; obesity; Obesity - pathology; adipocyte precursors; adipogenesis; CP: Metabolism; female obesity; high-fat diet; estrogen receptor alpha; estrogen signaling; estrous cycle; obesity; estradiol
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112390

White adipose tissue (WAT) distribution is sex dependent. Adipocyte hyperplasia contributes to WAT distribution in mice driven by cues in the tissue microenvironment, with females displaying hyperplasia in subcutaneous and visceral WAT, while males and ovariectomized females have visceral WAT (VWAT)-specific hyperplasia. However, the mechanism underlying sex-specific hyperplasia remains elusive. Here, transcriptome analysis in female mice shows that high-fat diet (HFD) induces estrogen signaling in adipocyte precursor cells (APCs). Analysis of APCs throughout the estrous cycle demonstrates increased proliferation only when proestrus (high estrogen) coincides with the onset of HFD feeding. We further show that estrogen receptor α (ERα) is required for this proliferation and that estradiol treatment at the onset of HFD feeding is sufficient to drive it. This estrous influence on APC proliferation leads to increased obesity driven by adipocyte hyperplasia. These data indicate that estrogen drives ERα-dependent obesogenic adipocyte hyperplasia in females, exacerbating obesity and contributing to the differential fat distribution between the sexes. [Display omitted] •HFD upregulates estrogen pathways in female APCs•Timing of HFD initiation in relation to the estrous cycle affects APC proliferation•ERα signaling is necessary for HFD-induced APC proliferation•Estrous cycle stage at the onset of HFD impacts adipocyte formation and obesity Saavedra-Peña et al. show that estradiol cycling regulates adipocyte formation in female mice by stimulating ERα-dependent proliferation of adipocyte precursor cells (APCs) at the onset of high-fat diet feeding. This estradiol-stimulated mechanism results in exacerbated obesity due to an increase in adipocyte formation.