Corticotropin-releasing hormone (CRH) transgenic mice display hyperphagia with increased Agouti-related protein mRNA in the hypothalamic arcuate nucleus

Shuichi Nakayama; Mitsuru Nishiyama; Yasumasa Iwasaki; Masayuki Shinahara; Yasushi Okada; Masayuki Tsuda; Mizuho Okazaki; Makoto Tsugita; Takafumi Taguchi; Shinya Makino; Mary P Stenzel-Poore; Kozo Hashimoto; Yoshio Terada

doi:10.1507/endocrj.K10E-370

ORIGINALS

Corticotropin-releasing hormone (CRH) transgenic mice display hyperphagia with increased Agouti-related protein mRNA in the hypothalamic arcuate nucleus

Shuichi Nakayama, Mitsuru Nishiyama, Yasumasa Iwasaki, Masayuki Shinahara, Yasushi Okada, Masayuki Tsuda, Mizuho Okazaki, Makoto Tsugita, Takafumi Taguchi, Shinya Makino, Mary P Stenzel-Poore, Kozo Hashimoto, Yoshio Terada

Author information

Shuichi Nakayama
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Mitsuru Nishiyama
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Yasumasa Iwasaki
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Masayuki Shinahara
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Yasushi Okada
Department of Laboratory Animal Science, Kochi Medical School, Kochi University, Nankoku, Japan
Masayuki Tsuda
Department of Laboratory Animal Science, Kochi Medical School, Kochi University, Nankoku, Japan
Mizuho Okazaki
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Makoto Tsugita
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Takafumi Taguchi
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Shinya Makino
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Mary P Stenzel-Poore
Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, USA
Kozo Hashimoto
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan
Yoshio Terada
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan

Keywords: Cushing’s syndrome, Appetite, Obesity, Glucocorticoid, Agouti-related protein

JOURNAL FREE ACCESS

2011 Volume 58 Issue 4 Pages 279-286

DOI https://doi.org/10.1507/endocrj.K10E-370

View "Advance Publication" version (March 5, 2011).

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Abstract

Although glucocorticoid-induced hyperphagia is observed in the patients with glucocorticoid treatment or Cushing’s syndrome, its molecular mechanism is not clear. We thus explored the expression of neuropeptide mRNAs in the hypothalamus related to appetite regulation in CRH over-expressing transgenic mice (CRH-Tg), a model of Cushing’s syndrome. We measured food intake, body weight (including body fat weight) and plasma corticosterone levels in CRH-Tg and their wild-type littermates (WT) at 6 and 14 weeks old. We also examined neuropeptide Y (NPY), proopiomelanocortin (POMC) and Agouti-related protein (AgRP) mRNAs in the arcuate nucleus (ARC) using in situ hybridization. Circulating corticosterone levels in CRH-Tg were markedly elevated at both 6 and 14 weeks old. Body fat weight in CRH-Tg was significantly increased at 14 weeks old, which is considered as an effect of chronic glucocorticoid excess. At both 6 and 14 weeks old, CRH-Tg mice showed significant hyperphagia compared with WT (14w old: WT 3.9±0.1, CRH-Tg 5.1±0.7 g/day, p<0.05). Unexpectedly, NPY mRNA levels in CRH-Tg were significantly decreased at 14 weeks old (WT: 1571.5±111.2, CRH-Tg: 949.1±139.3 dpm/mg, p<0.05), and there were no differences in POMC mRNA levels between CRH-Tg and WT. On the other hand, AgRP mRNA levels in CRH-Tg were significantly increased compared with WT at both ages (14w old: WT 365.6±88.6, CRH-Tg 660.1±87.2 dpm/ mg, p<0.05). These results suggest that glucocorticoid-induced hyperphagia is associated with increased hypothalamic AgRP. Our results also indicate that hypothalamic NPY does not have an essential role in the increased food intake during glucocorticoid excess.

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