Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner

• Published in: Nature communications 2024-08, Vol.15 (1), p.6622-21, Article 6622
• Main Authors: Steiner, Benjamin M., Benvie, Abigail M., Lee, Derek, Jiang, Yuwei, Berry, Daniel C.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/100; 13/106; 13/31; 13/51; 14/63; 17β-Estradiol; 45/77; 45/90; 631/136/532/2074; 631/443/319/2723; 631/532/2074; 631/80/86; 64/60; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipogenesis; Adipose tissue; Adipose Tissue, White - cytology; Adipose Tissue, White - metabolism; Adiposity; Animals; Antiestrogens; Body fat; Cell Proliferation; Cells (biology); Clonal deletion; CXCR4 protein; Deletion; Diet, High-Fat - adverse effects; Estradiol - metabolism; Estradiol - pharmacology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Females; High fat diet; Humanities and Social Sciences; Hypersensitivity; Lipodystrophy; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Peroxisome proliferator-activated receptors; PPAR gamma - genetics; PPAR gamma - metabolism; Progenitor cells; Receptors; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Science; Science (multidisciplinary); Sex Characteristics; Sex Factors; Sex hormones; Sexual dimorphism; Stem Cells - cytology; Stem Cells - metabolism; Steroid hormones; Steroids
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50985-8

Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ -expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4 -deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity. Sex steroid receptor activity controls the distribution and growth of adipose tissues. Here, the authors reveal that Cxcr4 regulates the Pparg-marked adipose lineage to restrict female fat mass by modifying estrogen receptor expression and activity.