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Urocortins and Cholecystokinin-8 Act Synergistically to Increase Satiation in Lean But Not Obese Mice: Involvement of Corticotropin-Releasing Factor Receptor-2 Pathway

Digestive Diseases Research Center and Center for Neurovisceral Sciences and Women’s Health, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073

Address all correspondence and requests for reprints to: Yvette Taché, Ph.D., Center for Neurovisceral Sciences and Women’s Health, CURE Building 115, Room 203, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: ytache{at}mednet.ucla.edu.

Interactions between gastrointestinal signals are a part of integrated systems regulating food intake (FI). We investigated whether cholecystokinin (CCK)-8 and urocortin systems potentiate each other to inhibit FI and gastric emptying (GE) in fasted mice. Urocortin 1 and urocortin 2 (1 µg/kg) were injected ip alone or with CCK (3 µg/kg) in lean, diet-induced obese (DIO) or corticotropin-releasing factor receptor-2 (CRF₂)-deficient mice. Gastric vagal afferent activity was recorded from a rat stomach-vagus in vitro preparation. When injected separately, urocortin 1, urocortin 2, or CCK did not modify the 4-h cumulative FI in lean mice. However, CCK plus urocortin 1 or CCK plus urocortin 2 decreased significantly the 4-h FI by 39 and 27%, respectively, compared with the vehicle + vehicle group in lean mice but not in DIO mice. Likewise, CCK-urocortin-1 delayed GE in lean but not DIO mice, whereas either peptide injected alone at the same dose had no effect. CCK-urocortin 2 suppression of FI was observed in wild-type but not CRF₂-deficient mice. Gastric vagal afferent activity was increased by intragastric artery injection of urocortin 2 after CCK at a subthreshold dose, and the response was reversed by devazepide. These data establish a peripheral synergistic interaction between CCK and urocortin 1 or urocortin 2 to suppress FI and GE through CRF₂ receptor in lean mice that may involve CCK modulation of gastric vagal afferent responsiveness to urocortin 2. Such synergy is lost in DIO mice, suggesting a resistance to the satiety signaling that may contribute to maintain obesity.

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