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 mice.