Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1

• Published in: Cell metabolism 2023-03, Vol.35 (3), p.438-455.e7
• Main Authors: González-García, Ismael, García-Clavé, Elena, Cebrian-Serrano, Alberto, Le Thuc, Ophélia, Contreras, Raian E., Xu, Yanjun, Gruber, Tim, Schriever, Sonja C., Legutko, Beata, Lintelmann, Jutta, Adamski, Jerzy, Wurst, Wolfgang, Müller, Timo D., Woods, Stephen C., Pfluger, Paul T., Tschöp, Matthias H., Fisette, Alexandre, García-Cáceres, Cristina
• Format: Article
• Language: English
• Subjects: Animals; ARC; Arcuate Nucleus of Hypothalamus; diet-induced obesity; estradiol; Estradiol - pharmacology; Female; hypothalamus; Hypothalamus - metabolism; leptin; Leptin - metabolism; Mice; Obesity - metabolism; Pomc; Pro-Opiomelanocortin - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2023.02.004

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. [Display omitted] •Global and hypothalamic Cited1 loss exacerbates diet-induced obesity in female mice•Cited1 is highly enriched in estradiol-sensitive melanocortin neurons•Hypothalamic Cited1 molecularly links the effects of E2 and leptin on food intake•Cited1 in PomcARC neurons acts as a downstream co-factor for E2-leptin signaling Estradiol regulates energy homeostasis by altering feeding behavior, but how this sex hormone converges with the melanocortin system is not fully understood. Here, González-García et al. discover that Cited1 acts as a crucial hypothalamic co-factor mediating the anti-obesity effects of estradiol through potentiation of leptin’s anorectic actions. This neuroendocrine mechanism represents a mode by which melanocortin neurons integrate energy stores with reproductive signals for metabolic adaptation in diet-induced obesity.