Leptin Receptor Expression in Mouse Intracranial Perivascular Cells.

Xuefeng Yuan,Alexandre Caron,Hua Wu,Laurent Gautron

doi:10.3389/fnana.2018.00004

Abstract

Past studies have suggested that non-neuronal brain cells express the leptin receptor. However, the identity and distribution of these leptin receptor-expressing non-neuronal brain cells remain debated. This study assessed the distribution of the long form of the leptin receptor (LepRb) in non-neuronal brain cells using a reporter mouse model in which LepRb-expressing cells are permanently marked by tdTomato fluorescent protein (LepRb-CretdTomato). Double immunohistochemistry revealed that, in agreement with the literature, the vast majority of tdTomato-tagged cells across the mouse brain were neurons (i.e., based on immunoreactivity for NeuN). Non-neuronal structures also contained tdTomato-positive cells, including the choroid plexus and the perivascular space of the meninges and, to a lesser extent, the brain. Based on morphological criteria and immunohistochemistry, perivascular cells were deduced to be mainly pericytes. Notably, tdTomato-positive cells were immunoreactive for vitronectin and platelet derived growth factor receptor beta (PDGFBR). In situ hybridization studies confirmed that most tdTomato-tagged perivascular cells were enriched in leptin receptor mRNA (all isoforms). Using qPCR studies, we confirmed that the mouse meninges were enriched in Leprb and, to a greater extent, the short isoforms of the leptin receptor. Interestingly, qPCR studies further demonstrated significantly altered expression for Vtn and Pdgfrb in the meninges and hypothalamus of LepRb-deficient mice. Collectively, our data demonstrate that the only intracranial non-neuronal cells that express LepRb in the adult mouse are cells that form the blood-brain barrier, including, most notably, meningeal perivascular cells. Our data suggest that pericytic leptin signaling plays a role in the integrity of the intracranial perivascular space and, consequently, may provide a link between obesity and numerous brain diseases.

Highlights

Leptin’s metabolic actions are mediated by its binding to the long-form of the leptin receptor (LepRb) within specific brain regions (Coppari et al, 2005; de Luca et al, 2005; Leinninger et al, 2009; Fernandes et al, 2015)
This study demonstrated that the only intracranial non-neuronal cells that express the leptin receptors are cells making up the blood-brain barrier, including subsets of meningeal perivascular cells, endothelial cells and choroid plexus suggesting the presence of pericytopathy
Emerging literature suggests that functional LepRb signaling occurs in astrocytes, tanycytes, ependymal cells, and microglia cells (Cottrell et al, 2009; Hsuchou et al, 2009b; Balland et al, 2014; Kim et al, 2014)

Summary

Introduction

Leptin’s metabolic actions are mediated by its binding to the long-form of the leptin receptor (LepRb) within specific brain regions (Coppari et al, 2005; de Luca et al, 2005; Leinninger et al, 2009; Fernandes et al, 2015). Leptin binding and mRNA for the short isoforms of the leptin receptor were both detected in the choroid plexus, meninges, astrocytes and the brain vasculature (Devos et al, 1996; Guan et al, 1997; Bjorbaek et al, 1998; Boado et al, 1998; Corp et al, 1998; Elmquist et al, 1998; Hileman et al, 2002; Carlo et al, 2007; Koga et al, 2014). Enrichment of vascular markers was recently reported in LepRb-expressing brain cells (Allison et al, 2015) In vitro, both microglial cells and astrocytes were shown to be responsive to leptin pre-treatment (Pinteaux et al, 2007; Lafrance et al, 2010; Fuente-Martin et al, 2012)

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