We examined core body temperature (CBT) of urocortin 1 (UCN1) and corticotropin releasing factor (CRF) knockout (KO) mice exposed to 4°C for 2？h. UCN1KO mice showed higher average CBT during cold exposure as compared to WT. The CBT of male and female WT mice dropped significantly to and ？C at 4°C, respectively. In contrast, the CBT of male and female UCN1KO mice dropped only slightly after 2？h at 4°C to and ？C, respectively. WT female and male UCN1KO mice showed significant acclimatization to cold; however, female UCN1KO mice did not show such a significant acclimatization. CRFKO mice showed a dramatic decline in CBT from at 22°C to at 4°C for 2？h. The CRF/UCN1 double KO (dKO) mice dropped their CBT to after 2？h exposure to 4°C. Dexamethasone treatment prevented the decline in CBT of the CRFKO and the dKO mice. Taken together, the data suggest a novel role for UCN1 in thermoregulation. The role of CRF is likely secondary to adrenal glucocorticoids, which have an important regulatory role on carbohydrate, fat, and protein metabolism. 1. Introduction Corticotropin releasing factor (CRF) [1] plays an essential role in the physiological regulation of the hypothalamic-pituitary-adrenal (HPA) as CRF knockout (KO) mice have low concentrations of corticosterone and decreased response to stress [2]. CRF is also found in several regions of the central nervous system (CNS) where it functions as a neurotransmitter and regulates several aspects of behavior particularly in response to stressful stimuli [3]. The urocortins, UCN1 [4], UCN2 [5], and UCN3 [6], are a family of peptides, which were discovered by their sequence homology to CRF, sauvagine [7], and urotensin 1 [8]. These peptides bind and activate the CRF receptors, CRFR1 [9] and CRFR2 [10], with different affinities and potencies. CRF binds to CRFR1 with a higher affinity than to CRFR2, whereas UCN1, sauvagine, and urotensin 1 interact with both receptors with a relatively similar affinity [10]. In contrast, UCN2 and UCN3 have higher affinity for CRFR2 than for CRFR1 [5, 6]. Therefore, the actions of UCN1 can be mediated by both CRF receptors [11]. In this regard, it has been shown that UCN1 mRNA levels are upregulated in the Edinger-Westphal (EW) nucleus of mice following stress exposure [12]. UCN1-deficient mice were shown to have a normal corticosterone response to acute immobilization stress [13, 14]; however, they showed anxiety-like behavior and impaired inner ear physiology [13]. UCN1KO mice were also shown to have decreased corticosterone response to cold and impaired adaptation to repeated
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