Maintaining energy homeostasis and storing calories when food is available is fundamental for survival. The hypothalamus is the key region of the brain that is required to maintain homeostasis. Several hypothalamic nuclei have been demonstrated to play essential roles in regulating food intake and body weight. The vagal innervation of key metabolic visceral organs including the liver, portal vein, and the small intestine is important in regulating energy balance. This chapter discusses several mechanisms illustrating how the central nervous system (CNS) responds to multiple hormonal and metabolic cues to regulate food intake, body weight, and glucose homeostasis. The ventromedial hypothalamic neurons (VMH) have historically been linked to the regulation of body weight. The vagus nerve innervates organs in the thoracic and the abdominal cavities. Central serotonin system is an important regulator of feeding, energy balance and glucose homeostasis.