Megalin mediates the transport of leptin across the blood-CSF barrier

Dietrich, Marcelo O.; Spuch, Carlos; Antequera, Dessire; Rodal, Izaskun; Yébenes, Justo Garcı́a de; Molina, José Antonio; Bermejo, F; Carro, Eva

doi:10.1016/j.neurobiolaging.2007.01.008

Cited by 169 publications

(155 citation statements)

References 56 publications

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“…LRP2 binds leptin to mediate leptin reuptake in renal tubules and to promote leptin transport across the choroid plexus [21][22][23] , suggesting a molecular link between LRP2 and leptin. LRP2 was also identified as an endocytic receptor for clusterin 24,25 and our preliminary data confirmed the mRNA expression of LRP2 in rodent hypothalamus.…”

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confidence: 99%

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

et al. 2013

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Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low-density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling.

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confidence: 99%

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

et al. 2013

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“…These data argue in favor of a crucial role for megalin in neuroprotection, and suggest that megalin dysfunction might be involved in the pathogenesis of sporadic AD. This latter idea is reinforced by the fact that megalin reduces with ageing [Carro et al, 2005;Dietrich et al, 2008], which, in turn, is the major risk factor in AD.…”

Section: Discussionmentioning

confidence: 99%

“…Megalin is also able to transcytose neurotrophic growth factors, including insulin-like growth factor I (IGF-I) [Carro et al, , 2005 which itself participates in many neuroprotective actions in the brain [Carro et al, , 2002Trejo et al, 2001]. Furthermore, in the CP megalin expression and function reduce with ageing and AD [Carro et al, 2005;Dietrich et al, 2008], suggesting that a dysfunction in megalin pathway could represent an important risk factor in the pathogenesis of AD.…”

Section: Introductionmentioning

confidence: 99%

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

Vargas

Bullido

Martínez-García

et al. 2010

American J of Med Genetics Pt B

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Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.

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“…[42][43][44][45] Endothelial cells in the B-BB and choroid plexus epithelial cells in the blood-CSF barrier are two important structures that control the entry of various regulatory proteins into the brain. 46 The extent to which these structures contribute to leptin homoeostasis in the CNS or to its reaching either the hypothalamus or targets in other areas of the brain is not known. The fact that CSF leptin levels are different (lower) than serum leptin level and the presence of leptin receptors in all areas of the brain require that peripheral leptin should be associated with the blood-CSF and B-BB transport systems in its entry into the brain.…”

Section: Leptin Transportmentioning

confidence: 99%

Leptin transport in the central nervous system

Ziylan

Baltacı

Moğulkoç

2009

Cell Biochemistry & Function

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Synthesized and released by the adipose tissue, leptin is the widely studied 167-amino acid hormonal protein product of the obesity gene. Originally leptin was defined in association with satiety and energy balance and claimed to be an anti-obesity factor that functioned via a feedback effect from adipocytes to hypothalamus. There is a growing body of evidence that emphasizes the importance of leptin in the regulation of food intake and body weight in animals and humans, alike. Other research findings point out that it plays a role in the regulation of the metabolism, sexual development, reproduction, hematopoiesis, immunity, gastrointestinal functions, sympathetic activation, and angiogenesis. The aim of this review is to evaluate the relation between leptin and the central nervous system (CNS).

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Megalin mediates the transport of leptin across the blood-CSF barrier

Cited by 169 publications

References 56 publications

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

Leptin transport in the central nervous system

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