Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice

The 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 miceThis research was funded by grants from Instituto de Salud Carlos III (PI15/01272 and PI18/00998) cofounded by FEDER, Fundación Mutua Madrileña, MINECO (MF: BFU2016-80899-P; ML: 2015-CP079; CD: BFU2017-87721; RN: BFU2015-70664R); Xunta de Galicia (ML: SAF2015-71026-R and 2016-PG068; RN: 2015-CP080 and 2016-PG057); Fundación BBVA (RN) and Fundación Atresmedia (RN and ML). Luisa M Seoane is a SERGAS-I3SNS researcher. CIBERobn is an iniciative of the ISCIII supported by FEDERS