Urocortin 3 into the ventromedial hypothalamus modulates feeding, blood glucose levels, and hypothalamic POMC gene expression but not the HPA axis. Am J Physiol Endocrinol Metab 298: E337-E345, 2010. First published December 1, 2009; doi:10.1152/ajpendo.00402.2009.-Urocortin 3 (Ucn 3) is a corticotropin-releasing factor (CRF)-related peptide with high affinity for the type 2 CRF receptor (CRFR2). Central administration of Ucn 3 stimulates the hypothalamic-pituitary-adrenal axis, suppresses feeding, and elevates blood glucose levels, suggesting that activation of brain CRFR2 promotes stress-like responses. Several CRFR2-expressing brain areas, including the ventromedial hypothalamus (VMH) and the posterior amygdala (PA), may be potential sites mediating the effects of Ucn 3. In the present study, Ucn 3 or vehicle was bilaterally injected into the VMH or PA, and food intake and plasma levels of ACTH, corticosterone, glucose, and insulin were determined. Food intake was greatly reduced in rats following Ucn 3 injection into the VMH. Ucn 3 injection into the VMH rapidly elevated plasma levels of glucose and insulin but did not affect ACTH and corticosterone secretion. Injection of Ucn 3 into the PA did not alter any of the parameters measured. We determined that the majority of CRFR2-positive neurons in the VMH were excitatory glutamatergic, and a subset of these neurons project to the arcuate nucleus of the hypothalamus (ARH). Importantly, stimulation of CRFR2 in the VMH increased proopiomelanocortin mRNA expression in the ARH. In conclusion, the present study demonstrates that CRFR2 in the VMH mediates some of the central effects of Ucn 3, and the ARH melanocortin system may be a downstream target of VMH CRFR2 neurons.corticotrophin-releasing factor; urocortin; feeding; hypothalamus; blood glucose; hypothalamic-pituitary-adrenal axis UROCORTIN 3 (Ucn) 3 is a member of the CRF peptide family identified in humans and rodents (20,31). It displays high affinity for the type 2 CRF receptor (CRFR2) with minimal affinity for the type 1 CRF receptor (CRFR1) (20, 31). Thus Ucn 3 has been considered as an endogenous ligand for CRFR2. In the brain, Ucn 3-expressing neurons are located primarily in the hypothalamus and the amygdala (31, 33). Within the hypothalamus, the majority of Ucn 3-positive neurons are found in the rostral part of the perifornical area with moderate levels of Ucn 3-positive cells found in the median preoptic nucleus (33). Ucn 3-immunoreactive nerve fibers and terminals are distributed mostly in the forebrain areas, including the hypothalamus and limbic system, where prominent Ucn 3 fibers are found in the lateral septum, amygdala, and the bed nucleus of stria terminalis (BNST) (33). In the hypothalamus, Ucn 3 fibers predominately innervate the ventromedial nucleus (VMH), with moderate levels of innervation found in medial preoptic area and the ventral premammillary nucleus (33). These anatomical features suggest that central Ucn 3 may be involved in multiple physiological and behavioral regulations.Simi...