Syndecan‐3 Modulates Food Intake by Interacting with the Melanocortin/AgRP Pathway

Procter Gamble Pharmaceuticals, Inc, Health Care Research Center, Mason, Ohio 45040, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 07/2003; 994(1):66-73. DOI: 10.1111/j.1749-6632.2003.tb03163.x
Source: PubMed


Syndecan-3, expressed in the developing nervous system and adult brain, alters feeding behavior through its interaction with the CNS melanocortin system, which provides critical tonic inhibition of both food intake and body adipose stores. A variety of both in vitro and transgenic data supports the hypothesis that syndecan-3 modulates melanocortin activity via syndecan-3 facilitation of agouti-related protein (AgRP), a competitive antagonist of alpha-melanocyte-stimulating hormone (alpha-MSH) at the melanocortin-3 and -4 receptors. Consistent with this hypothesis, mice lacking syndecan-3, which therefore would be predicted to have less effective AgRP, are more sensitive to inhibition of food intake by the melanocortin agonist MTII. Additionally, we took advantage of the fact that syndecan-3 facilitation of AgRP is limited to when it is bound to the cell membrane. Pharmacologic inhibition of the enzyme that cleaves syndecan-3 from the cell membrane leads to increased food intake in fasted rats, which have elevated levels of AgRP. Furthermore, the shedding process appears to be regulated under physiologic conditions, because a putative inhibitor of the shedding process, tissue inhibitor of metalloprotease-3 (TIMP-3), is increased by food deprivation. These observations contribute to the hypothesis that syndecan-3 regulation of melanocortin signaling contributes to the normal control of energy balance. Collectively, the data suggest that the modulation of melanocortin regulation of energy balance by syndecan-3 is modulated by the action of a TIMP-3-sensitive metalloprotease.

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    • "Syndecan-3 Knock-Out mice, in common with other syndecan-KO animals, develop normally and only under conditions of challenge or insult are different phenotypes observed 6. Syndecan-3 is mainly found in the nervous system and has been shown to be a co-receptor for a number of important growth factors, including Agouti related protein (AgRP), heparin binding growth associated molecule (HB-GAM), glial cell line derived growth factor (GDNF), neurturin (NRTN), artemin (PSPN) and NOTCH, via interactions with its HS chains 10– 14. Interactions with AgRP, an antagonist of melanocortin, lead to altered feeding behaviours in the syndecan-3 null mouse 14, 15. In addition, syndecan-3 deficiency leads to the mice exhibiting more addictive behaviours to opiates such as cocaine, and this occurs as a result of its interaction with GDNF 16. "
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    ABSTRACT: Syndecan-3 is one of the four members of the syndecan family of heparan sulphate proteoglycans and has been shown to interact with numerous growth factors via its heparan sulphate chains. The extracellular core proteins of syndecan-1,-2 and -4 all possess adhesion regulatory motifs and we hypothesized that syndecan-3 may also possess such characteristics. Here we show that a bacterially expressed GST fusion protein consisting of the entire mature syndecan-3 ectodomain has anti-angiogenic properties and acts via modulating endothelial cell migration. This work identifies syndecan-3 as a possible therapeutic target for anti-angiogenic therapy.
    Full-text · Article · Dec 2013 · F1000 Research
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    • "Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of HS chains that are constituents of syndecan-3. This mechanism, along with previously proposed, modulated shedding of syndecan-3 ectodomain [13], [16], [17], [18], constitutes a novel signaling system that will help improve our understanding of obesity and its causes. "
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    ABSTRACT: Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.
    Full-text · Article · Mar 2012 · PLoS ONE
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    • "Syndecan-3 Null allele: viable; altered feeding behavior (Strader et al. 2004); no phenotype in synovial endothelial cells (Patterson et al. 2005); enhanced long-term potentiation (LTP) in area CA1 (brain) and impaired performance in tasks assessing hippocampal function (Kaksonen et al. 2002); more sensitive to inhibition of food intake by the melanocortin agonist MTII (Reizes et al. 2003); perturbs laminar structure of the cerebral cortex as a result of impaired radial migration, and neural migration in the rostral migratory stream is impaired (Hienola et al. 2006); novel form of muscular dystrophy characterized by impaired locomotion, fibrosis, and hyperplasia of myonuclei and satellite cells (Cornelison et al. 2004). "
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    ABSTRACT: Heparan sulfate proteoglycans are found at the cell surface and in the extracellular matrix, where they interact with a plethora of ligands. Over the last decade, new insights have emerged regarding the mechanism and biological significance of these interactions. Here, we discuss changing views on the specificity of protein-heparan sulfate binding and the activity of HSPGs as receptors and coreceptors. Although few in number, heparan sulfate proteoglycans have profound effects at the cellular, tissue, and organismal level.
    Preview · Article · Jun 2011 · Cold Spring Harbor perspectives in biology
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