ESPEYB20 12. The Year in Science and Medicine Basic Research (3 abstracts)
12.11. Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1
Gonzalez-Garcia I , Garcia-Clave E , Cebrian-Serrano A , Le Thuc O , Contreras RE , Xu Y , Gruber T , Schriever SC , Legutko B , Lintelmann J , Adamski J , Wurst W , Muller TD , Woods SC , Pfluger PT , Tschop MH , Fisette A & Garcia-Caceres C
Cell Metabolism 35, 438–455, 2023. https://doi.org/10.1016/j.cmet.2023.02.004
Brief summary: This basic science study in mice shows how melanocortin neurons integrate reproductive signaling with energy homeostasis. In melanocortin neurons, estradiol (E2) enhances the anorectic action of leptin. Cited1 is enriched in these neurons and its loss exacerbates diet-induced obesity in female mice. Using several specific mouse models it is demonstrated how hypothalamic Cited1, via ERα and Stat3 interactions, link the effects of E2 and leptin on food intake.
It is well known that leptin deficiency leads to obesity and hypogonadotropic hypogonadism in both sexes. In addition, existence of a sex-specific crosstalk between the reproductive system and energy homeostasis is also established. Female mammals, including humans, seem quite protected against metabolic diseases by E2 during their reproductive years, but are at higher risk of diet-induced obesity after menopause when E2 production is lost.
However, the exact interplay between the two endocrine regulatory systems was not known. More so perhaps because of the difference in the nature of the signaling pathways by which they act. Leptin, a peptide hormone, acts on membrane receptors at the cell surface signaling through JAK/STAT. By contrast E2, a steroid hormone, binds mostly to nuclear receptors (e.g. ERα) which then regulate gene transcription. But the group of Gonzalez-Garcia et al based their study on the finding that both hormones are specifically expressed in the same melanocortin neurons in the hypothalamus. They found that Cited1 is the mediator between leptin-JAK/STAT and E2/ERα to enhance POMC transcription and inhibit food intake.
Understanding of the mechanism how E2 regulates leptin sensitivity in melanocortin neurons is essential for the development of novel, sex-specific treatment options against diet-induced obesity. This knowledge might even lead to an explanation for diet-induced obesity in some women in whom variants in the involved genes are found.
Results of this study and its significance were summarized in a Spotlight article (1).
Reference: 1. Estradiol and leptin: no engagement without CITED1. Olga Barca-Mayo and Miguel López. Trends in Endocrinology & Metabolism, July 2023, Vol. 34, No. 7. https://doi.org/10.1016/j.tem.2023.04.002.
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ESPE Yearbook of Paediatric Endocrinology
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