Dietary protein restriction increases hepatic leptin receptor mRNA and plasma soluble leptin receptor in male rodents.

Riho Yamada,Taku Kato,Yori Ozaki-Masuzawa,Keigo Matsuo,Tasuku Watanabe,Shizuka Odamaki,Asako Takenaka,Masaya Araki,Kaito Uchida,François Blachier

doi:10.1371/journal.pone.0219603

Abstract

Leptin is an adipokine that regulates adipose tissue mass through membrane-anchored leptin receptor (Ob-R). Extracellular domain of Ob-R in plasma is called soluble leptin receptor (sOb-R), and is the main leptin-binding protein. Based on a previous DNA microarray analysis that showed induction of hepatic Ob-R mRNA in low-protein diet-fed mice, this study aimed to clarify the effect of dietary protein restriction on hepatic Ob-R mRNA and plasma sOb-R levels. First, the effect of protein restriction on hepatic Ob-R mRNA level was examined together with fasting and food restriction using male rats as common experimental model for nutritional research. Hepatic Ob-R mRNA level was increased by feeding low-protein diet for 7 d, although not significantly influenced by 12-h fasting and sixty percent restriction in food consumption. Then, effect of protein restriction on liver Ob-R and plasma sOb-R was investigated using male mice because specific sOb-R ELISA was more available for mice. Hepatic Ob-R mRNA level was also increased in protein restricted-mice although it did not increase in hypothalamus. Hepatic Ob-R protein was decreased, whereas plasma sOb-R was increased by protein restriction. Because the concentration of sOb-R increased without changing plasma leptin concentration, free leptin in plasma was significantly reduced. The direct effect of amino acid deprivation on Ob-R mRNA level was not observed in rat hepatoma cells H4IIE cultured in amino acid deprived medium. In conclusion, dietary protein restriction increased hepatic Ob-R mRNA, resulting in increased plasma sOb-R concentration, which in turn, reduces plasma free leptin level and may modulate leptin activity.

Highlights

Leptin was discovered as a satiety factor, predominantly secreted from adipose tissues and known to maintain adequate fat reserve [1, 2]
In the first half of this study, we investigated the regulation of Ob-R mRNA using rats as a commonly used animal model in nutritional research, and we used mice in the latter half since the specific soluble leptin receptor (sOb-R) ELISA Kit was more available for mice than for rats
We clarified that protein restriction is a predominant regulator of hepatic Ob-R mRNA compared to fasting and food restriction

Summary

Introduction

Leptin was discovered as a satiety factor, predominantly secreted from adipose tissues and known to maintain adequate fat reserve [1, 2]. At least 6 Ob-R isoforms, named Ob-Ra–Ob-Rf, have been described and are products of alternative mRNA splicing from a single gene [8, 9] Among these isoforms, only Ob-Rb has complete length, containing all the motifs required for signal transduction and can fully activate the janus kinase/signal transducers and activators of transcription (JAK/STAT) intracellular signaling pathway [10]. Leptin reduces appetite via Ob-Rb in hypothalamus by suppressing the expression and secretion of neuropeptide Y and agouti-related peptide, and enhancing the synthesis of pro-opiomelanocortin [10]. It reduces energy expenditure by activating sympathetic nervous system [13]. Peripheral tissues have been reported to express mRNA for short isoforms of Ob-R [14, 15], which may exert central nervous system-independent effect of leptin [15]

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Conclusion