Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice.

María García-Palacios,Rubén Nogueiras,Luisa Seoane,Edward Milbank,Carlos Diéguez,Cintia Folgueira,Daniel Beiroa,Cecilia Castelao,Felipe Casanueva,María González-Rellán,Miguel López,Begoña Porteiro

doi:10.3390/nu11040752

Abstract

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.

Highlights

Obesity is characterized by a deregulation of numerous pathways involved in the energy homeostasis modulation
In an interesting way, when administrated in obese mice previously treated with UGN for four days, leptin induced a significant decrease in body weight (Figure 1D) as in food intake after 6 h (Figure 1E) and 24 h (Figure 1F)
Leptin was ICV injected in chow diet fed lean mice, and we were able to observe that leptin at the dose of 3 μg induced a decrease in body weight (Figure 1G) and in food intake after six and 24 h (Figure 1H–I)

Summary

Introduction

Obesity is characterized by a deregulation of numerous pathways involved in the energy homeostasis modulation. In order to maintain the body weight at stable levels, the central nervous system (CNS) is constantly informed about the status of the organism’s energy stores by peripheral systems through complex pathways. The gastrointestinal-brain axis has been described as a key player in all this metabolic homeostasis regulation [1]. Uroguanylin (UGN) has been recently proposed to be one of the members of this gut-brain axis implicated in body weight regulation [2,3,4,5,6]. It has been shown that UGN could bind GUCY2C at a hypothalamic level inducing the activation of anorexigenic pathways [6].

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Conclusion