title: Hyperphagia alters expression of hypothalamic 5-HT2C and 5-HT1B receptor genes and plasma des-acyl ghrelin levels in Ay mice.
abstract: The central melanocortin (MC) pathway is suggested to mediate satiety signaling downstream of serotonin (5-HT)2C receptors. 5-HT2C receptor mutant mice consume more food, which leads to late-onset obesity and impaired glucose tolerance. Ay mice with ectopic expression of the agouti peptide, which leads to a perturbation of the central MC pathway, develop obesity and diabetes, associated with low levels of plasma total ghrelin. Here, we report that 5-wk-old Ay mice consumed more food in association with decreases in levels of plasma des-acyl ghrelin, but not active ghrelin, and increases in hypothalamic 5-HT2C and 5-HT1B receptor gene expression compared with wild-type mice matched for age and body weight. These alterations were also observed in 8-wk-old obese Ay mice. Restricted feeding significantly decreased hypothalamic 5-HT2C and 5-HT1B receptor gene expression in association with a reversal of the decreases in plasma des-acyl ghrelin levels in 5-wk-old Ay mice. Moreover, restricted feeding reduced body weight, hyperinsulinemia, and hyperglycemia in association with increases in plasma des-acyl ghrelin levels in 8-wk-old obese Ay mice. Administration of m-chlorophenylpiperazine and fenfluramine, both of which induce anorexic effects via 5-HT2C receptors and/or 5-HT1B receptors, suppressed food intake in 5- and 8-wk-old Ay mice, whereas the anorexic effects were attenuated in food-restricted Ay mice. These findings suggest that the agouti peptide down-regulates hypothalamic 5-HT2C and 5-HT1B receptor gene expression under restricted feeding conditions, whereas chronic hyperphagia increases the expression of these genes and decreases plasma des-acyl ghrelin levels in Ay mice.
authors.affiliation: Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryou-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. knonogaki-tky@umin.ac.jp
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nonogaki
authors.forename: Kana
authors.initials: K
authors.lastname: Nozue
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
mesh_terms: D054366:Agouti Signaling Protein; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D031204:Caloric Restriction; D004435:Eating / Q000187:drug effects; D005277:Fenfluramine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin; D006963:Hyperphagia / Q000097:blood* / Q000235:genetics*; D007031:Hypothalamus / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D036361:Peptide Hormones / Q000097:blood*; D010879:Piperazines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D054366:Agouti Signaling Protein; D001786:Blood Glucose; D005277:Fenfluramine; D054439:Ghrelin; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D036361:Peptide Hormones; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044405:Receptor, Serotonin, 5-HT2C; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C422650:ghrelin, des-n-octanoyl; C015068:1-(3-chlorophenyl)piperazine