The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin.

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Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_E35252EEC91C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin.
Journal
Metabolism
Author(s)
Avendaño M.S., Perdices-Lopez C., Guerrero-Ruiz Y., Ruiz-Pino F., Rodriguez-Sanchez A.B., Sanchez-Tapia M.J., Sobrino V., Pineda R., Barroso A., Correa-Sáez A., Lara-Chica M., Fernandez-Garcia J.C., García-Redondo A.B., Hernanz R., Ruiz-Cruz M., Garcia-Galiano D., Pitteloud N., Calzado M.A., Briones A.M., Vázquez M.J., Tena-Sempere M.
ISSN
1532-8600 (Electronic)
ISSN-L
0026-0495
Publication state
Published
Issued date
08/2024
Peer-reviewed
Oui
Volume
157
Pages
155932
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Obesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1-encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown.
A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models.
MiR-137/325 repressed human KISS1 3'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats.
Our data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity.
Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity.
Keywords
MicroRNAs/genetics, MicroRNAs/metabolism, Hypogonadism/genetics, Hypogonadism/metabolism, Hypogonadism/complications, Kisspeptins/genetics, Kisspeptins/metabolism, Animals, Obesity/metabolism, Obesity/complications, Obesity/genetics, Male, Rats, Hypothalamus/metabolism, Humans, Mice, Rats, Wistar, Comorbidity, Comorbidities, Kiss1, Kisspeptins, Male hypogonadism, MicroRNAs, Obesity, Obesity-induced hypogonadism, miR-137, miR-325
Pubmed
Web of science
Create date
16/05/2024 15:31
Last modification date
26/07/2024 7:01
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