Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty.
OBJECTIVE
Puberty is a key developmental phenomenon highly sensitive to metabolic modulation. Worrying trends of changes in the timing of puberty have been reported in humans. These might be linked to the escalating prevalence of childhood obesity and could have deleterious impacts on later (cardio-metabolic) health, but their underlying mechanisms remain unsolved. The neuropeptide α-MSH, made by POMC neurons, plays a key role in energy homeostasis by mediating the actions of leptin and likely participates in the control of reproduction. However, its role in the metabolic regulation of puberty and interplay with kisspeptin, an essential puberty-regulating neuropeptide encoded by Kiss1, remain largely unknown. We aim here to unveil the potential contribution of central α-MSH signaling in the metabolic control of puberty by addressing its role in mediating the pubertal effects of leptin and its potential interaction with kisspeptin.


METHODS
Using wild type and genetically modified rodent models, we implemented pharmacological studies, expression analyses, electrophysiological recordings, and virogenetic approaches involving DREADD technology to selectively inhibit Kiss1 neurons, in order to interrogate the physiological role of a putative leptin→α-MSH→kisspeptin pathway in the metabolic control of puberty.


RESULTS
Stimulation of central α-MSH signaling robustly activated the reproductive axis in pubertal rats, whereas chronic inhibition of melanocortin receptors MC3/4R, delayed puberty, and prevented the permissive effect of leptin on puberty onset. Central blockade of MC3/4R or genetic elimination of kisspeptin receptors from POMC neurons did not affect kisspeptin effects. Conversely, congenital ablation of kisspeptin receptors or inducible, DREADD-mediated inhibition of arcuate nucleus (ARC) Kiss1 neurons resulted in markedly attenuated gonadotropic responses to MC3/4R activation. Furthermore, close appositions were observed between POMC fibers and ARC Kiss1 neurons while blockade of α-MSH signaling suppressed Kiss1 expression in the ARC of pubertal rats.


CONCLUSIONS
Our physiological, virogenetic, and functional genomic studies document a novel α-MSH→kisspeptin→GnRH neuronal signaling pathway involved in transmitting the permissive effects of leptin on pubertal maturation, which is relevant for the metabolic (and, eventually, pharmacological) regulation of puberty onset.
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofia (HURS), 14004 Córdoba, Spain.
Maria
M
Manfredi-Lozano
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofia (HURS), 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Córdoba, Spain. Electronic address: roarivas@gmail.com.
Juan
J
Roa
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofia (HURS), 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Córdoba, Spain.
Francisco
F
Ruiz-Pino
Centre for Neuroendocrinology and Department of Physiology, Otago School of Medical Sciences, University of Otago, 9054 Dunedin, New Zealand.
Richard
R
Piet
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain.
David
D
Garcia-Galiano
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain.
Rafael
R
Pineda
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain.
Aurora
A
Zamora
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain.
Silvia
S
Leon
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Córdoba, Spain.
Miguel A
MA
Sanchez-Garrido
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain.
Antonio
A
Romero-Ruiz
Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
Carlos
C
Dieguez
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofia (HURS), 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Córdoba, Spain.
Maria Jesus
MJ
Vazquez
Centre for Neuroendocrinology and Department of Physiology, Otago School of Medical Sciences, University of Otago, 9054 Dunedin, New Zealand.
Allan E
AE
Herbison
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofia (HURS), 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Córdoba, Spain.
Leonor
L
Pinilla
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofia (HURS), 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Córdoba, Spain. Electronic address: fi1tesem@uco.es.
Manuel
M
Tena-Sempere
DREADDs; Kisspeptin; Leptin; Metabolism; Puberty; α-MSH
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