Leptin acts on several circuits in the brain to regulate food intake and energy expenditure. In particular it has been shown that leptin can activate proopiomelanocortin neurons and inhibit agouti-related peptide neurons. Mice made obese by chronic consumption of a high fat diet have melanocortin systems that are unresponsive to leptin, and have structural changes in the hypothalamus that make the neural circuits less able to detect circulating endocrine and nutrient signals. Non-melanocortin circuits in the brains of obese mice remain leptin sensitive, even in obesity, and may mediate some of the pathology of obesity. Genetic deletion of negative regulators of leptin action enhances resistance to dietary obesity. Here I will discuss leptin action on the melanocortin circuits of lean and obese mice, and the effects of enhancing leptin action.