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Hyperphagia Alters Expression of Hypothalamic 5-HT2C and 5-HT1B Receptor Genes and Plasma Des-Acyl Ghrelin Levels in A^y Mice

Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan

Address all correspondence and requests for reprints to: Katsunori Nonogaki M.D., Ph.D., Associate Professor, 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. E-mail: knonogaki-tky{at}umin.ac.jp.

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. A^y 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 A^y 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 A^y 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 A^y 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 A^y 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 A^y mice, whereas the anorexic effects were attenuated in food-restricted A^y 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 A^y mice.

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