Obesity is the result of an imbalance between energy intake and energy expenditure. Under most circumstances, the increased availability of nutrients is tightly coupled with nutrient-sensing mechanisms that in turn activate appropriate behavioral and metabolic responses. The latter responses include decreases in food intake and the production of endogenous nutrients and increased expenditure of energy. The availability of nutrients can be sensed at central sites (mostly in the hypothalamus) or directly in peripheral tissues such as skeletal muscle and fat. The hypothalamus links the sensing of nutrients to the control of metabolism and feeding behavior. Here, we discuss how two central and peripheral nutrient-sensing mechanisms participate in this complex feedback system.