Heparanase Affects Food Intake and Regulates Energy Balance in Mice

Linda Karlsson-Lindahl,Suzanne L Dickson,Magdalena Taube,Ying-Xia Tan,Caroline Hansson,Therese Admyre,John-Olov Jansson,Linnéa Schmidt,Israel Vlodavsky,Emil Egeciouglu,David Haage,Jin-Ping Li,Ulf Lindahl

doi:10.1371/journal.pone.0034313

Linda Karlsson-Lindahl, Suzanne L Dickson + Show 11 more

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https://doi.org/10.1371/journal.pone.0034313

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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.

Highlights

Obesity and overweight continue to increase world-wide, with severe health consequences that pose heavy economic burdens on society [1]
The melanocortin receptor ligands, a-melanocyte stimulating hormone (a-MSH) and agouti-related peptide (AgRP), modulate downstream homeostatic signaling via their action at melanocortin receptors MC3R and MC4R
The results indicate that heparanase inhibits obesity by degrading HS chains, presumably linked to syndecan-3, thereby suppressing the binding of AgRP to MC4R

Summary

Introduction

Obesity and overweight continue to increase world-wide, with severe health consequences that pose heavy economic burdens on society [1]. The balance between food intake and energy expenditure is monitored and tightly regulated by the central nervous system. The melanocortin receptor ligands, a-melanocyte stimulating hormone (a-MSH) and agouti-related peptide (AgRP), modulate downstream homeostatic signaling via their action at melanocortin receptors MC3R and MC4R. The agonist a-MSH reduces appetite and increases energy expenditure [4]. These effects are opposed by AgRP, an obesity-inducing peptide that operates as an inverse agonist at MC4R in vitro and in vivo [5]. Mice and humans that lack a-MSH or have defective MC4R signaling are hyperphagic, obese and show increased linear growth [6,7,8]. A defective MC4R is the most common cause of inherited severe obesity [12]

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