In rodents, hypocretin (HCRT, also called orexin) influences a variety of endocrine, autonomic and metabolic functions. The present study was undertaken to determine whether the HCRT-producing circuit is involved in the hypothalamic regulation of homeostasis in primates as well. Female monkeys (Cercopithecus aethiops) were studied that were either fed or fasted for 24 h. Immunocytochemistry revealed HCRT-producing perikarya exclusively in the lateral hypothalamus-perifornical region and dorsomedial hypothalamus of the monkey brain. HCRT axons and axon terminals were present in different parts of the hypothalamus and adjacent forebrain and thalamic nuclei. The 24 h fast resulted in an aproximate 50% decline in circulating leptin levels and significantly elevated c-fos expression in the perifornical region, dorsomedial, ventromedial and arcuate nuclei and in the medial preoptic area. In the dorsomedial nucleus and perifornical region of fasted monkeys, three times more HCRT-neurons expressed nuclear c-fos than those of the normally-fed controls. Neurons in different parts of the hypothalamus and basal forebrain that expressed c-fos, but were non-HCRT-containing, were targets of HCRT-immunopositive boutons establishing asymmetric synapses. In the arcuate nucleus, subsets of these HCRT-targeted c-fos-expressing cells contained neuropeptide Y. The present study provides the first experimental evidence to implicate HCRT in the hypothalamic regulation of homeostasis in primates. The fact that these lateral hypothalamic cells have leptin receptors and can be activated by a metabolic challenge and that they innervate diverse brain regions indicates that the HCRT system may be a key integrator of environmental cues in their regulation of diverse brain activity.