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Corticotropin-Releasing Factor-Overexpressing Mice Exhibit Reduced Neuronal Activation in the Arcuate Nucleus and Food Intake in Response to Fasting

Center for Ulcer Research and Education (CURE): Digestive Diseases Research Center and Center for Neurobiology of Stress (A.S., M.G., M.M., Y.T., L.W.), Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073; Department of Molecular Microbiology and Immunology (M.P.S.-P.), Oregon Health and Science University, Portland, Oregon 97239; Department of Medicine (P.K.), Division Psychosomatic Medicine and Psychotherapy, Charité, Campus Mitte, Universitätsmedizin Berlin, 10117 Berlin, Germany; and Department of Medicine and Institute of Neurogastroenterology (H.M.), Martin Luther Hospital, 14193 Berlin, Germany

Address all correspondence and requests for reprints to: Lixin Wang, Ph.D., Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 11301 Wilshire Boulevard, Building 115, Room 117, Los Angeles, California 90073. E-mail: lixinwang{at}mednet.ucla.edu.

Corticotropin-releasing factor (CRF) overexpressing (OE) mice are a genetic model that exhibits features of chronic stress. We investigated whether the adaptive feeding response to a hypocaloric challenge induced by food deprivation is impaired under conditions of chronic CRF overproduction. Food intake response to a 16-h overnight fast and ip injection of gut hormones regulating food intake were compared in CRF-OE and wild type (WT) littermate mice along with brain Fos expression, circulating ghrelin levels, and gastric emptying of a nonnutrient meal. CRF-OE mice injected ip with saline showed a 47 and 44% reduction of 30-min and 4-h cumulative food intake response to an overnight fast, respectively, compared with WT. However, the 30-min food intake decrease induced by ip cholecystokinin (3 µg/kg) and increase by ghrelin (300 µg/kg) were similar in CRF-OE and WT mice. Overnight fasting increased the plasma total ghrelin to similar levels in CRF-OE and WT mice, although CRF-OE mice had a 2-fold reduction of nonfasting ghrelin levels. The number of Fos-immunoreactive cells induced by fasting in the arcuate nucleus was reduced by 5.9-fold in CRF-OE compared with WT mice whereas no significant changes were observed in other hypothalamic nuclei. In contrast, fasted CRF-OE mice displayed a 5.6-fold increase in Fos-immunoreactive cell number in the dorsal motor nucleus of the vagus nerve and a 34% increase in 20-min gastric emptying. These findings indicate that sustained overproduction of hypothalamic CRF in mice interferes with fasting-induced activation of arcuate nucleus neurons and the related hyperphagic response.