Proposed effects of heparanase on MC4R signaling.

HS chains of a cell-surface HSPG serve as co-receptors for AgRP, and at the same time preclude access of α-MSH to the MC4R. (Left panel) In the absence of heparanase (Hpa-ko) the HS chains remain intact, resulting in continuous AgRP-induced activation of MC4R, thus promoting food consumption, fat accumulation, and a positive energy balance. Under these conditions α-MSH signaling is severely restricted. (Right panel) HS chains are degraded by overexpressed heparanase (Hpa-tg), thus rendering the MC4R accessible to α-MSH, whereas AgRP devoid of its HS co-receptor is unable to engage the MC4R and thus remains inactive. This setting explains the acute effects of ICV-injected heparanase that lead to transient yet drastic reduction in feeding. However, it is also compatible with the long-term effects of transgenic heparanase expression that shift energy balance toward increased loss of body fat and compensatory up-regulation of appetite.