Urocortin III Is Expressed in Pancreatic β-Cells and Stimulates Insulin and Glucagon Secretion

Abstract

Urocortin (Ucn) III, or stresscopin, is a high affinity ligand for the type 2 corticotropin-releasing factor (CRFR2) receptor recently identified in rodents and human. Ucn III was initially identified as a neuropeptide expressed in discrete areas in the brain. In the present study, we demonstrate that Ucn III is expressed in pancreatic beta-cells and in a mouse beta-cell line, MIN6. Ucn III secretion from the cells was measured using a highly specific RIA, and we found that high potassium, forskolin, or high glucose can stimulate Ucn III secretion from these cells. In vivo studies showed that rats receiving an iv Ucn III injection had a significant elevation of plasma glucagon followed by plasma glucose levels compared with rats receiving vehicle. Ucn III injections also result in an increase in plasma insulin levels. The observed effects of Ucn III were blocked by pretreatment with a CRFR2 antagonist, astressin(2)-B. Furthermore, Ucn III stimulated glucagon and insulin release from isolated rat islets, and astressin(2)-B abolished the effects of Ucn III, in keeping with a CRFR2-mediated mechanism. Taken together, the present studies suggest pancreatic Ucn III acting through CRFR2 is involved in the local regulation of glucagon and insulin secretion.

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

“…The dorsomedial VMN is rich with CRF 2 receptors (Van Pett et al, 2000) and Ucn 3 terminals (Li et al, 2003), and medial parvocellular (Chalmers et al, 1995) or magnocellular PVN neurons (Van Pett et al, 2000) also reportedly express moderate CRF 2 mRNA levels. Single-unit recording studies of hypothalamic slices found that stresscopin-related peptide, structurally related to Ucn 2, alters firing rates of neurons in the VMN and PVN, supporting their functional sensitivity to CRF 2 stimulation (Davidowa and Plagemann, 2004).…”

“…Accordingly, the VMN mediates counter-regulatory responses to hypoglycemia and energy balance responses to leptin (Jacob et al, 1997;Satoh et al, 1997;Choi et al, 1999;Dube et al, 1999;Elias et al, 2000;Borg et al, 2003). VMN CRF 2 mRNA levels are upregulated by leptin, and pancreatic beta-cell Ucn 3-CRF 2 signaling is responsive to extracellular glucose levels (Li et al, 2003), suggesting a homeostatic role for Ucn 3 in responses to short-and long-term fuel availability. Consistent with this view, Zucker fa/fa rats, food-deprived adult rats (Timofeeva and Richard, 1997) and infant rats separated from their dams (Eghbal-Ahmadi et al, 1997), all conditions of perceived energy insufficiency, show decreased VMN CRF 2 mRNA levels.…”

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

“…It is expressed abundantly and exclusively in mouse beta-cells [82] (Figure 2). Recently, it was reported to be expressed relatively late in the beta-cell lineage during mouse development [55,77].…”

“…While mouse UCN3 is restricted to beta-cells [56,82], its expression in macaque (Macaca nemestrina) and human islets extends to the alpha-cell [56] (Figures 1 and 2).…”

Corticotropin-releasing hormone physiology

“…Using a two part search strategy of the human DNA database, a third CRH-like peptide was identified and named stresscopin (also termed urocortin III) (15)(16)(17) (18,19), with a third gene described in the catfish (20). Both receptors consist of seven transmembrane regions coupled to adenylate cyclase via G s .…”