Folgueira Cobos, CintiaBeiroa Tarrío, DanielGonzález Rellán, María JesúsPorteiro Couto, BegoñaMilbank, EdwardCastelao Taboada, CeciliaGarcía Palacios, MaríaCasanueva Freijo, FelipeLópez Pérez, Miguel A.Diéguez González, CarlosSeoane Camino, Luisa MaríaNogueiras Pozo, Rubén2020-10-302020-10-302019Folgueira, C.; Beiroa, D.; González-Rellán, M.J.; Porteiro, B.; Milbank, E.; Castelao, C.; García-Palacios, M.; Casanueva, F.F.; López, M.; Diéguez, C.; Seoane, L.M.; Nogueiras, R. Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice. Nutrients 2019, 11, 752.http://hdl.handle.net/10347/23511The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regulation. Uroguanylin (UGN) has been recently proposed to be a part of this gut-brain axis regulating food intake, body weight and energy expenditure. Expression of UGN is regulated by the nutritional status and dependent on leptin levels. However, the exact molecular mechanisms underlying this UGN-leptin metabolic regulation at a hypothalamic level still remains unclear. Using leptin resistant diet-induced obese (DIO) mice, we aimed to determine whether UGN could improve hypothalamic leptin sensitivity. The present work demonstrates that the central co-administration of UGN and leptin potentiates leptin’s ability to decrease the food intake and body weight in DIO mice, and that UGN activates the hypothalamic signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositide 3-kinases (PI3K) pathways. At a functional level, the blockade of PI3K, but not STAT3, blunted UGN-mediated leptin responsiveness in DIO mice. Overall, these findings indicate that UGN improves leptin sensitivity in DIO miceeng© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/UroguanylinLeptinFood intakeBody weightHypothalamusjournal article10.3390/nu110407522072-6643open access