title: Heparanase affects food intake and regulates energy balance in mice.
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.
authors.affiliation: Institute of Neuroscience and Physiology/Endocrinology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Linda.Lindahl@gu.se
authors.forename: Linda
authors.initials: L
authors.lastname: Karlsson-Lindahl
authors.forename: Linnéa
authors.initials: L
authors.lastname: Schmidt
authors.forename: David
authors.initials: D
authors.lastname: Haage
authors.forename: Caroline
authors.initials: C
authors.lastname: Hansson
authors.forename: Magdalena
authors.initials: M
authors.lastname: Taube
authors.forename: Emil
authors.initials: E
authors.lastname: Egecioglu
authors.forename: Emil
authors.initials: E
authors.lastname: Egeciouglu
authors.forename: Ying-xia
authors.initials: YX
authors.lastname: Tan
authors.forename: Therese
authors.initials: T
authors.lastname: Admyre
authors.forename: John-Olov
authors.initials: JO
authors.lastname: Jansson
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.forename: Ulf
authors.initials: U
authors.lastname: Lindahl
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Dickson
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D003433:Crosses, Genetic; D004041:Dietary Fats; D004435:Eating / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism / Q000235:genetics; D005247:Feeding Behavior; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005966:Glucuronidase / Q000494:pharmacology*; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D053670:Syndecan-3 / Q000378:metabolism; D000521:alpha-MSH / Q000378:metabolism; D000099175:Heparanase
chemical_list: D054369:Agouti-Related Protein; D004041:Dietary Fats; D005966:Glucuronidase; D044105:Receptor, Melanocortin, Type 4; D053670:Syndecan-3; D000521:alpha-MSH; D000099175:Heparanase; C515199:Agrp protein, mouse; C574273:MC4R protein, mouse