ECE2019 Oral Communications Reproduction 1 (5 abstracts)
Conditional ablation of AMP-Activated Protein Kinase (AMPK) in GnRH neurons reveals specific roles in reproductive and metabolic homeostasis
Juan Roa 1, , Delphine Franssen 1 , Alexia Barroso 1, , Francisco Ruiz-Pino 1, , María Jesús Vázquez 1, , David García-Galiano 1, , Juan Manuel Castellano 1, , Francisco Gaytán 1, , Carlos Diéguez 2, , Leonor Pinilla 1, , Miguel López 2, & Manuel Tena-Sempere 1,
1Department of Cell Biology, Physiology and Immunology, University of Córdoba; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba, Spain; 2CIBER Fisiopatología de la Obesidad y Nutrición, Madrid, Spain; 3Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain.
Reproduction is tightly coupled to body energy and metabolic status. GnRH neurons, the final output pathway for the brain control of reproduction, directly or indirectly receive and integrate multiple signals, including metabolic cues regulating reproductive function. Yet, the molecular underpinnings of such phenomenon remain largely unfolded. AMP-activated protein kinase (AMPK), a fundamental cellular sensor that becomes activated in conditions of energy deficit, has a key role in the control of whole-body metabolism. Fragmentary evidence suggests that AMPK participates also in the control of key elements of the reproductive axis, as Kiss1 neurons, driving an inhibitory valence in situations of energy depletion. However, the physiological contribution of AMPK signaling in GnRH neurons to the metabolic control of reproduction is unknown. We report herein the characterization of the first mouse line, named GAMKO, with conditional ablation of a1-AMPK in GnRH neurons. In keeping with a putative inhibitory action of AMPK in GnRH neurons, GAMKO females displayed earlier puberty onset and exaggerated LH (as surrogate marker of GnRH) responses to kisspeptin-10 at the prepubertal age. In adulthood, GAMKO females retained increased LH responsiveness to kisspeptin and the neurokinin-B agonist, Senktide, and showed partial resilience to the inhibitory effects of conditions of negative energy balance on the gonadotropic axis. Thus, GAMKO females submitted to chronic subnutrition showed a faster recovery of estrus cyclicity after re-feeding. Furthermore, elimination of AMPK from GnRH neurons prevented the physiological drop of LH level after fasting and changed the pattern of LH pulsatility. The modulatory role of AMPK in GnRH neurons seems to require estradiol, since no changes in basal LH levels or pulsatility were detected in ovariectomized GAMKO mice subjected to fasting or subnutrition. Notably, AMPK ablation on GnRH neurons caused also alterations in body composition, with increased fat mass, and modest changes in insulin and glucose tolerance in GAMKO females. In sum, our data document a physiological role of AMPK signaling in GnRH neurons in the metabolic control of the reproductive axis, as conduit of at least part of the inhibitory actions of energy deficit. In addition, our results disclose a putative function of AMPK specifically in GnRH neurons in the control of body composition and glucose homeostasis, whose relevance warrants further investigation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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