In the hypothalamus, there are several types of neurons expressing specific neuropeptides which modulate instinctive behaviors and physiological conditions. Among them, orexin neurons are known to be involved in the regulation of wakefulness and energy homeostasis. While past studies have revealed the role of orexin peptide, orexin neurons contain not only orexin but also other neurotransmitters such as glutamate and dynorphin. In this study, we examined the physiological role of orexin neurons by pharmacogenetic activation utilizing designer receptors exclusively activated by designer drugs (DREADD). We generated novel orexin-Cre mice and utilized Cre-dependent adeno-associated virus (AAV) vectors to express Gq-coupled modified GPCR, hM3Dq. Pharmacogenetic stimulation of orexin neurons simultaneously increased locomotive activity, food intake, water intake and the respiration exchange ratio (RER). Elevation of blood glucose levels and RER persisted even after locomotion and feeding behaviors returned to basal levels. In order to further examine the physiological roles of orexin neurons, we also performed selective ablation of orexin neurons by utilizing a Cre-dependent AAV vector which expresses diphtheria toxin A. Accordantly, 83% ablation of orexin neurons resulted in decreased food and water intake, while 70% ablation had almost no effect on these parameters. Our results show the integral role of orexin neurons in regulation of feeding behavior and metabolism and indicate its robustness.