Energy homeostasis is maintained by the balance between energy intake (food intake) and energy expenditure, when the former exceeds the latter, one becomes obesity. The hypothalamus is the center of controlling food intake and energy expenditure by integrating information from hormones and nutrients. FoxO1 is a downstream effector of insulin signaling and Sirt1 is an NAD(+)-dependent deacetylase, both of which work as energy sensors at the cellular level. In this review, I focused on hypothalamic FoxO1 and Sirt1 in the regulation of energy metabolism. Meanwhile, recent studies have suggested that hypothalamic inflammation and ER stress cause leptin/insulin resistance, which predisposes to diet-induced obesity.