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Urocortin III is a neuropeptide hormone and member of the corticotropin-releasing factor (CRF) family which includes mammalian CRF , urocortin , urocortin II , frog sauvagine, and piscine urotensin I.1 Mouse urocortin III shares 90, 40, 37, and 18% identity to human urocortin III , mouse urocortin II , human urocortin , and mouse urocortin, respectively. It is expressed in the hypothalamus, brainstem, lateral septum (LS)/bed nucleus of stria terminalis (BnST) in the CNS and the small intestine, pancreatic β-cells, and skin in the periphery in mice. Urocortin III selectively binds to type 2 CRF receptors (Kis = 5, 1.8, and >100 nM for rat CRF2α, rat CRF2β, and human CRF1, respectively). It stimulates cAMP production in CHO cells expressing rat CRF2α and mouse CRF2β (EC50s = 0.073 and 0.08 nM, respectively) as well as in cultured anterior pituitary cells expressing endogenous CRF2β. In vivo, urocortin III (2 μg, i.p.) accelerates metamorphosis of S. hammondii tadpoles.2 Urocortin III (20 μg, i.c.v.) increases exploration in the open field test and decreases latency to enter the lit compartment in the dark-light emergence test in mice, indicating anxiolytic-like activity, and mRNA expression is increased in mouse brain in response to restraint.3 It is co-released with insulin to potentiate glucose-stimulated somatostatin release in vitro and in vivo in wild-type mice, however, it is depleted from β-cells in mouse and macaque models of type 2 diabetes, suggesting a role in glycemic control.4

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