Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1

Area of Science:

• Neuroendocrinology
• Metabolic disease research
• Molecular endocrinology

Background:

• Women exhibit lower metabolic disease risk before menopause, suggesting a protective role for sex hormones.
• Estrogen and leptin signaling synergy is known to protect against metabolic disturbances, but mechanisms are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms of crosstalk between estradiol and leptin signaling in the hypothalamus.
• To identify key factors mediating the protective effects of sex hormones against metabolic diseases.

Main Methods:

• Utilized embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models.
• Investigated the role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1).
• Analyzed interactions between Cited1, estrogen receptor alpha (ERα), and Stat3 in pro-opiomelanocortin (Pomc) neurons.

Main Results:

• Identified a novel role for hypothalamic Cited1 in mediating estradiol (E2)-dependent leptin actions on feeding.
• Demonstrated that Cited1 acts as a co-factor in Pomc neurons, integrating E2 and leptin signaling through Cited1-ERα-Stat3 interactions.
• Showed Cited1 mediates leptin's anorectic effects within arcuate Pomc neurons.

Conclusions:

• Cited1 is a key mediator of the crosstalk between the gonadal (estradiol) and adipose (leptin) axes in the hypothalamus.
• Melanocortin neurons integrate these endocrine signals via Cited1, contributing to sexual dimorphism in diet-induced obesity.
• Findings provide new molecular insights into sex-based differences in metabolic health and obesity.