Effects of fatty acid metabolites on nocturia

Tatsuya Ihara,Masayuki Takeda,Norifumi Sawada,Takahiko Mitsui,Sachiko Tsuchiya,Yoichi Shinozaki,Satoru Kira,Hiroshi Shimura,Mie Kanda,Eiji Shigetomi,Schuichi Koizumi

doi:10.1038/s41598-022-07096-5

Abstract

Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (ClockΔ19/Δ19) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in ClockΔ19/Δ19 mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in ClockΔ19/Δ19 than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.

Highlights

Dysregulation of circadian rhythm can cause nocturia
Lower urinary tract functions follow a circadian rhythm regulated by clock genes; for example, circadian bladder capacity is related to Connexin 43 expression rhythm in bladder smooth muscle[5], and circadian urinary sensation is related to the rhythms of mechanosensitive ion channels in bladder urothelial cells[6,7,8,9], which is an integral part of a sensory receptor[10]
Levels of fatty acid metabolites changed with circadian rhythm in the sera of wild‐type (WT) mice and deteriorated in those of Clock mutant mice (ClockΔ19/Δ19)

Summary

Introduction

Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; the reason remains unknown. We investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. We investigated the association between serum metabolites and nocturia in the elderly using metabolomics analysis In this pilot study, the levels of some fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Zdocosahexaenoic acid (4-HDoHE), were shown to be higher in the plasma of patients with nocturia than in that of those without n octuria[17]. The identified fatty acid metabolites, including PEA, 9-HODE, and 4-HDoHE, may be involved in the development of nocturia with a background of circadian rhythm disorder. We investigated the circadian changes in the levels of serum fatty acid metabolites and their effects on voiding behavior, such as nocturia, in mice. The results obtained may lead to the novel effect of lipids on lower urinary tract function and a new pathology for nocturia

Methods

Results

Conclusion