Hypothalamic SIRT1-mediated regulation of the hormonal trigger of ovulation and its repression in energy deficit

• Published in: Metabolism, clinical and experimental clinical and experimental, 2025-03, Vol.164, p.156125, Article 156125
• Main Authors: Vazquez, María J., Daza-Dueñas, Silvia, Velasco, Inmaculada, Ruiz-Pino, Francisco, Sanchez-Tapia, María J., Manfredi-Lozano, María, Torres-Granados, Carmen, Barroso, Alexia, Roa, Juan, Sánchez-Garrido, Miguel A., Dieguez, Carlos, Lomniczi, Alejandro, Nogueiras, Rubén, Tena-Sempere, Manuel
• Format: Article
• Language: English
• Subjects: Animals; Energy Metabolism; Female; Female reproduction; GnRH; Hypothalamus - metabolism; Kiss1; Kisspeptins; Kisspeptins - genetics; Kisspeptins - metabolism; Mice; Mice, Inbred C57BL; Neurons - metabolism; Ovulation; Ovulation - physiology; Rats; SIRT1; Sirtuin 1 - genetics; Sirtuin 1 - metabolism
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2024.156125

Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypothalamic SIRT1, a key component of the epigenetic machinery that links nutritional status and puberty onset via modulation of Kiss1, plays a critical role in the control of the preovulatory surge of gonadotropins, i.e., the hormonal trigger of ovulation, and its repression by conditions of energy deficit. Kiss1 neurons in the preoptic area, with proven roles in the control of ovulation, express Sirt1 mRNA. Reciprocal changes in hypothalamic SIRT1 content and Kiss1 expression were observed during the pre-ovulatory phase in adult female rats. Central activation of SIRT1 reduced Kiss1 expression in the rostral hypothalamus, and attenuated the preovulatory surge, while blockade of central SIRT1 augmented it. Conditions of energy deficit enhanced hypothalamic SIRT1 activity and caused suppression of the pre-ovulatory surge and ovulation, which could be rescued by central SIRT1 inhibition. In turn, virogenetic induction of SIRT1 in rostral hypothalamic Kiss1 neurons in adult female mice disrupted ovarian cyclicity and suppressed reproductive indices, despite preserved body weight. Our data document the prominent function of hypothalamic SIRT1 as a key modulator of Kiss1 neurons and the hormonal surge driving ovulation in adulthood, with a major role in its inhibition during conditions of energy insufficiency. The metabolic sensor, SIRT1, operating in Kiss1 neurons at the rostral hypothalamus (i.e., Kiss1AVPV neurons), plays a major role in the control of the hormonal trigger of ovulation, namely, the preovulatory surge of gonadotropins, and its suppression under situations of energy deficiency. Conditions of activation of hypothalamic SIRT1 (left panels), due to undernutrition, pharmacological (SA3) intervention or virogenetic overexpression of Sirt1 in Kiss1AVPV neurons suppresses the preovulatory surge of gonadotropins, likely via inhibition of Kiss1 expression, and impairs several reproductive indices. In turn, in conditions of fasting (right panels), which blunted the preovulatory surge of LH and suppressed ovulation, pharmacological inhibition (EX527) of SIRT1 rescued the preovulatory surge and reversed the ovulatory failure, despite persistent conditions of energy deficit. All in all, these data supports a major function of SIRT1 in the neuro