Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1

Ismael González-García, Elena García-Clavé, Alberto Cebrian-Serrano, Ophélia Le Thuc, Raian E. Contreras, Yanjun Xu, Tim Gruber, Sonja C. Schriever, Beata Legutko, Jutta Lintelmann, Jerzy Adamski, Wolfgang Wurst, Timo D. Müller, Stephen C. Woods, Paul T. Pfluger, Matthias H. Tschöp, Alexandre Fisette, Cristina García-Cáceres

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.

Original languageEnglish
Pages (from-to)438-455.e7
JournalCell Metabolism
Volume35
Issue number3
DOIs
StatePublished - 7 Mar 2023

Keywords

  • ARC
  • Pomc
  • diet-induced obesity
  • estradiol
  • hypothalamus
  • leptin

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