There are still unanswered questions about the mechanism(s) of action of GC-C in neuronal circuits, how the GC-C system integrates orexigenic and anorexigenic signals to control energy expenditure and energy balance, and how central GC-C signaling modulates peripheral tissue functionality and obesity pathophysiology. This evidence concerns the gene GUCY2C and obesity due to melanocortin 4 receptor deficiency.