Leptin acts on several circuits in the brain, to regulate food intake and energy expenditure. In particular it has been shown that leptin can activateproopiomelanocortin neurons and inhibit agouti-related peptide neurons. It has also been recently shown that a portion of leptin action on energy balance is lost when mice lack leptin receptors on just POMC neurons, or have genetic or pharmacological blockade of the melanocortin system. Furthermore, loss of leptin actions on the melanocortin system caused disruption in glycemic control. Thus the melanocortin system is a necessary mediator of part of leptin action on energy balance, and somehow contributes to normal glucose homeostasis. We have recently demonstrated that mice made obese by chronic consumption of a high fat diet have melanocortin systems that are unresponsive to leptin. Low fat diet reverses this leptin resistance, and reestablishes normal glycemic control. Here I will discuss leptin and glucose sensing in the melanocortin circuits of lean and obese mice. I will also describe how over-activity of the melanocortin pathways might contribute to cachexia.