In young healthy individuals, bodily adipose content or size is homeostatically maintained over the long-term by the control of a precise balance between energy or food intake versus energy expenditure. An essential component of this feedback system is the need for the body to monitor or sense adipose size. Leptin, which is produced in and released from adipose in direct proportion to its size, provides such a signal, and initiates its homeostatic responses largely via binding to leptin receptors (LepR) in the hypothalamus. It is well established that decreases in hypothalamic LepR binding signals starvation, leading to hunger and reduced energy expenditure. Conversely, in some situations, increases in hypothalamic LepR binding can suppress food intake and increase energy expenditure. However, the specific hypothalamic sites and mechanisms are incompletely understood, in particular for the role of leptin in the control of energy expenditure. The purpose of this review is to develop a framework for the complex neurocircuitry and mechanisms by which increases (or decreases) in leptin increase (or decrease) energy expenditure, which consists of the resting metabolic rate (RMR), physical activity, and thermogenesis. The RMR, in turn, is set largely by the hypothalamic pituitary thyroid (HPT) axis, whereas heat released from brown adipose tissue (BAT) contributes significantly to thermogenesis. Therefore, we focus particularly on the mechanisms by which leptin activates the HPT axis and brown adipose tissue (BAT). We will further consider how this regulation is engaged or modified by challenges such as starvation, hypothermia, obesity, and pregnancy.