FGF21 increases water intake, urine output and blood pressure in rats.

Tod Turner,Alan Opsahl,Magalie Boucher,Matthew Zahner,Xian Chen,Bryan Goodwin,Mylène Perreault,George DeMarco,Jean-Claude Dussaule

doi:10.1371/journal.pone.0202182

Abstract

Fibroblast growth factor 21 (FGF21) is a hormone secreted by the liver in response to metabolic stress. In addition to its well-characterized effects on energy homeostasis, FGF21 has been shown to increase water intake in animals. In this study, we sought to further explore the effects of FGF21 on fluid homeostasis in rats. A single dose of a long-acting FGF21 analog, PF-05231023, significantly increased water consumption, which was accompanied by an elevation in urine output that appeared prior to a significant change in water intake. We observed that FGF21 rapidly and significantly increased heart rate and blood pressure in telemeter-implanted rats, before changes in urine output and water intake were observed. Our data suggest that sympathetic activation may contribute to the pathogenesis by which FGF21 increases blood pressure as the baroreceptor unloading induced reflex tachycardia was significantly elevated in FGF21-treated animals. However, FGF21 was still capable of causing hypertension in animals in which approximately 40% of the sympathetic post-ganglionic neurons were ablated. Our data suggest that FGF21-induced water intake is in fact secondary to diuresis, which we propose to be a compensatory mechanism engaged to alleviate the acute hypertension caused by FGF21.

Highlights

Fibroblast growth factor 21 (FGF21) is a peptide hormone secreted by the liver that modulates metabolism and growth in response to metabolic stress
Despite reducing the consumption of sweetened and alcoholic solutions, two studies have reported that FGF21 significantly increased water intake, which could be blunted by selective deletion of KLB in the brain, and suggested a potential role for FGF21 in the regulation of fluid homeostasis [13, 15]
In contrast to the reported weight loss effects observed in several species, we did not detect any significant change in food intake or body weight in our studies (Figs 2E and 4D, respectively)

Summary

Introduction

Fibroblast growth factor 21 (FGF21) is a peptide hormone secreted by the liver that modulates metabolism and growth in response to metabolic stress. Despite reducing the consumption of sweetened and alcoholic solutions, two studies have reported that FGF21 significantly increased water intake, which could be blunted by selective deletion of KLB in the brain, and suggested a potential role for FGF21 in the regulation of fluid homeostasis [13, 15]. If electrolyte concentrations (osmolality) fall outside physiologic ranges, the body rapidly responds by releasing hormones (arginine vasopressin (AVP), angiotensin II, aldosterone, etc) and modulating the autonomic nervous system in order to regulate fluid output to normalize electrolyte levels. It has been suggested that FGF21 could be involved in the hormonal and/or neuronal regulation of fluid homeostasis as FGF21 transgenic overexpression was reported to impair hypothalamic AVP expression and its circadian regulation [9, 16]. We provide a detailed characterizion of the effect of FGF21 on fluid homeostasis and explore potential mechanisms underlying these observations

Results

Discussion

Ethics statement