Heparanase affects food intake and regulates energy balance in mice.

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)

Nyckelord

Agouti-Related Protein

metabolism

Animals

Body Composition

Body Weight

Crosses

Genetic

Dietary Fats

Eating

genetics

physiology

Energy Metabolism

genetics

Feeding Behavior

Female

Gene Expression Regulation

Enzymologic

Glucuronidase

pharmacology

Infusions

Intraventricular

Male

Mice

Mice

Inbred C57BL

Mice

Knockout

Receptor

Melanocortin

Type 4

genetics

metabolism

Signal Transduction

Syndecan-3

metabolism

alpha-MSH

metabolism

agouti-related protein

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)