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Central Nesfatin-1 Reduces Dark-Phase Food Intake and Gastric Emptying in Rats: Differential Role of Corticotropin-Releasing Factor₂ Receptor

Department of Medicine (A.S., M.G., L.W., N.W.G.L., Y.T.), CURE, Center for Neurobiology of Stress, Digestive Diseases Division, University of California, Los Angeles, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California 90073; Peptide Biology Laboratories (J.R.), Salk Institute, La Jolla, California 92037; Clinic for Psychosomatic Medicine (P.K.), Charité-Universitätsmedizin Berlin, D-10117 Berlin, Germany; and Department of Medicine and Institute of Neurogastroenterology (H.M.), Martin-Luther-Hospital, D-14193 Berlin, Germany

Address all correspondence and requests for reprints to: Yvette Taché, Ph.D., Center for Neurovisceral Sciences and Women’s Health CURE, Building 115, Room 117, Veterans Administration Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: ytache{at}mednet.ucla.edu.

Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 µg/rat, icv) decreased 2–3 h and 3–6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 µg/rat) had no effect. The corticotropin-releasing factor (CRF)₁/CRF₂ antagonist astressin-B or the CRF₂ antagonist astressin₂-B abolished icv nesfatin-1’s anorexigenic action, whereas an astressin₂-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv astressin₂-B. Nesfatin-1 into the 4v (0.05 µg/rat) or ic (0.5 µg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic astressin₂-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF₂-receptor-dependent pathways after forebrain injection and CRF₂-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.