ESPEYB21 1. Pituitary and Neuroendocrinology Novel Genes (5 abstracts)
1.8. The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin
Avendaño MS , Perdices-Lopez C , Guerrero-Ruiz Y , Ruiz-Pino F , Rodriguez-Sanchez AB , Sanchez-Tapia MJ , Sobrino V , Pineda R , Barroso A , Correa-Sáez A , Lara-Chica M , Fernandez-Garcia JC , García-Redondo AB , Hernanz R , Ruiz-Cruz M , Garcia-Galiano D , Pitteloud N , Calzado MA , Briones AM , Vázquez MJ & Tena-Sempere M
Metabolism. 2024 Aug;157:155932. doi: j.metabol.2024.155932. PubMed:38729600
Brief Summary: This study provides evidence for the role of miR-137/325 in obesity-induced hypogonadism (OIH) and metabolic dysfunction.
Obesity is associated with different forms of gonadal and reproductive dysfunction, including central male hypogonadism (1, 2). Although weight loss is the ideal therapeutic strategy for patients with OIH, significant weight loss is usually difficult to achieve only with lifestyle changes. Hence, androgen administration is often necessary in the management of OIH (3). Although the mechanisms involved in OIH are not well-defined, and compelling, yet fragmentary evidence has suggested the potential role of alterations of the hypothalamic Kiss1 system. It has been reported that obesity causes downregulation of receptors regulating kisspeptin neurons, which is associated with a decreased LH pulse frequency, lower LH concentrations, and hypogonadism (4).
This study investigated the mechanisms underlying OIH in males, focusing on the role of microRNAs (miRNAs) miR-137 and miR-325 in repressing hypothalamic kisspeptin expression. Various bioinformatics tools, expression and functional analyses were used to assess the impact of miR-137/325 on kisspeptin expression and the subsequent effects on reproductive and metabolic health.
The study demonstrates that miR-137 and miR-325 are upregulated in obesity, decreasing the kisspeptin expression in the hypothalamus causing low LH and testosterone concentrations. Significant improvements were achieved in both reproductive and metabolic outcomes in obese rats by reversal of this suppression. They showed that 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, with the improvement of glucose intolerance, insulin resistance, and cardiovascular and inflammatory markers. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats.
In conclusion, the miR-137/325-kisspeptin pathway plays an important role in the pathogenesis of OIH and metabolic comorbidities, representing a potential therapeutic target for OIH in men.
References: 1. Bombardieri A, Bufano A, Fralassi N, Ciuoli C, Benenati N, Dalmiglio C, et al. Assessing the Prevalence of Male Obesity-Associated Gonadal Dysfunction in Severe Obesity: A Focus on the Impact of Bariatric Surgery and Surgical Approaches. Obes Surg. 2024;34(9):3434-44.2. Molina-Vega M, Muñoz-Garach A, Damas-Fuentes M, Fernández-Garcúa JC, Tinahones FJ. Secondary male hypogonadism: A prevalent but overlooked comorbidity of obesity. Asian J Androl. 2018;20(6):531-8.3. Shenoy MT, Mondal S, Fernandez CJ, Pappachan JM. Management of male obesity-related secondary hypogonadism: A clinical update. World J Exp Med. 2024;14(2):93689.4. Villa PA, Ruggiero-Ruff RE, Jamieson BB, Campbell RE, Coss D. Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice. J Neurosci. 2024;44(28).
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ESPE Yearbook of Paediatric Endocrinology
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