The adipocyte derived hormone leptin is a peripheral signal that informs the brain about the metabolic status of an organism. Although traditionally viewed as an appetite suppressing hormone, studies in the past decade have highlighted the role of leptin in energy expenditure. Leptin has been shown to increase energy expenditure in particular through its effects on the cardiovascular system and brown adipose tissue (BAT) thermogenesis via the hypothalamus. The current review summarizes the role of leptin signaling in various hypothalamic nuclei and its effects on the sympathetic nervous system to influence blood pressure, heart rate and brown adipose tissue thermogenesis. Specifically, the role of leptin signaling on three different hypothalamic nuclei, the dorsomedial hypothalamus, the ventromedial hypothalamus, and the arcuate nucleus, is reviewed. It is known that all these brain regions influence the sympathetic nervous system activity and thereby regulate BAT thermogenesis and the cardiovascular system. Thus, the current work focuses on how leptin signaling in specific neuronal populations within these hypothalamic nuclei influences certain aspects of energy expenditure.