2007 Fiscal Year Final Research Report Summary
Molecular mechanism in the control of central obesity and atherosclerosis by androgen and its target molecule
| Project/Area Number |
17109009
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Endocrinology
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| Research Institution | Kyushu University |
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Principal Investigator |
NAWATA Hajime Kyushu University, Graduate School of Medical Sciences, Professor (10038820)
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| Co-Investigator(Kenkyū-buntansha) |
YANASE Toshihiko KYUSHU UNIVERSITY, Graduate School of Medical Sciences, Associate Professor (30239818)
OKABE Taijiro Kyushu University, Hospital, Assistant Professor (40264030)
NOMURA Masatoshi Kyushu University, Hospital, Assistant Professor (30315080)
NISHI Yoshihiro Kurume University, Hospital, Lecturer (20352122)
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| Project Period (FY) |
2005 – 2007
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| Keywords | androgen receptor / leptin / obesity / atherosclerosis / selective androgen receutor modulator / dehydroepiandrosterone |
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| Research Abstract |
(1)The central mechanism of androgen-androgen receptor(AR)activity in obesity: Hypogonadism is linked with the increase in fat mass in male humans. AR null male mice (ARL/Y) develop late-onset obesity. We revealed that AR deletion in male mice results in weakened leptin-induced food intake suppression and a drop in body weight. In wild type(WT)males, AR is highly expressed in various hypothalamic nuclei, which also express a long-form leptin receptor(OBRB), and co-resides with OBRB directly in arcuate neurons. In vitro, AR significantly enhances leptin-induced STAT3 transactivation of leptin target genes including POMC and SOCS3. AR also enhances STAT3 nuclear translocation induced by leptin in vitro. ARL/Y mice receiving leptin showed impaired STAT3 nuclear localization in arcuate neurons. These findings identify AR as acting at the hypothalamus as a regulator of central leptin-OBRB-STAT3 signaling, and identify a physiological role for AR in energy homeostasis in male subjects. (2) A
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ndrogens and atherosclerosis: We obtained results indicating that endogenous dihydrotestosterone (DHT)is protective against atherosclerosis. Male ApoE/AR double null mice were more atherosclerotic than male ApoE null ones, a type of atherosclerosis model that is independent of serum lipid level. High-cholesterol diet-induced atherosclerosis in New Zealand white rabbit was aggravated by testectomy; however, this was dramatically improved by DHT administration. (3) Development of a selective androgen receptor modulator(SARM): We searched for a SARM that may confer benefits for energy homeostasis. We identified a chemical as a promising candidate. This chemical, unlike DHT, hardly stimulated PSA expression in prostate cancer cells; whereas it dramatically reduced the plasma triglyceride level. (4) Analysis of DDSP-transgenic (TG) mice: DHEA induces MAP kinase phosphatase, designated DDSP, as one of its target molecules. We generated mice carrying a DDSP transgene. DDSP-Tg mice weighed less than WT mice when supplied a high fat diet. While no difference in food-intake or movement distance was found between DDSP-Tg and WT mice, oxygen consumption of DDSP-Tg mice was higher than that of WT. This suggested an increase of basal metabolism in DDSP-Tg mice. The anti-obesity effect of DHEA might be, at least in part, mediated through DDSP. Less
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[Journal Article] Androgens and Metabolic Syndrome : Lessons from Androgen Receptor Knock Out (ARKO) Mice.2008
Author(s)
Yanase,T., Fan, W., Kyoya, K., Min, L., Takayanagi, R., Kato, S., Nawata H
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Journal Title
J Steroid Biochem Molec Biol (in press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] IGF1/insulin signaling activates androgen signaling through direct interactions of Foxol with androgen receptor.2007
Author(s)
Fan, W., Yanase, T., Morinaga, H., Okabe, T., Nomura, M., Daitoku, H., Fukamizu, A., Kato, S., Takayanagi, R., Nawata H
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Journal Title
J Biol Chem 282
Pages: 7329-38
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The pituitary function of androgen receptor constitutes a glucocorticoid production circuit.2007
Author(s)
Miyamoto, J., Matsumoto, T., Shiina, H., Inoue, K., Takada, I., Iro, S., Itoh, J., Minematsu, T., Sato, T., Yanase, T., Nawata,H., Osamura, YR., Kato S
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Journal Title
Mol Cell Biol 27
Pages: 4807-14
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of the functional domains of ANT-1, a novel coactivator of the androgen receptor2006
Author(s)
Fan, S., Goto,K., Chen, G., Morinaga, H., Nomura, M., Okabe, T., Nawata, H., Yanase T
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Journal Title
Biochem Biophys Res Commum 341
Pages: 192-201
Description
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[Journal Article] Impaired nuclear translocation, nuclear matrix targeting and intranuclear mobility of mutant androgen receptors earring amino acid substitutions in the deoxyribonucleic acid-binding domain derived from androen insensitivity syndrome patients.2005
Author(s)
Kawate, H., Wu, Y., Ohnaka, K., Tao, R-H., Nakamura, K., Okabe, T., Yanase, T., Nawata, H., Takayanagi R
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Journal Title
J Clin Endocrinol Metab 90
Pages: 6162-6169
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Modulation of androgen receptor transactivation by FoxHl : A newly identified androgen receptor corepressor.2005
Author(s)
Chen, G., Nomura, M., Morinaga, H., Matsubara, E., Okabe, T., Goto, K., Yanase,T., Zheng, H., Lu, J., Nawata H
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Journal Title
J Biol Chem 280
Pages: 36355-63
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Dehydroepiandrosterone negatively regulates the p38 mitogen-activated protein kinase pathway by a novel PTPN7 locus-derived transcript.2005
Author(s)
Ashida, K., Goto, K., Zhao, Y., Okabe, T., Yanase, T., Takayanagi, R., Nomura, M., Nawata H
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Journal Title
Biochim Biophys Acta(Gene Structure Exper) 1728(1-2)
Pages: 84-94
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghreln.2005
Author(s)
Nishi, Y., Hosoda, H., Mori, K., Kaiya, H., Sato, T., Fukue, Y., Fukushima, N., Yanase, T., Nawata, H., Kangawa, K., KojimaM
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Journal Title
Endocrinology 146
Pages: 2255-64
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Androgen receptor null male mice develop late-onset obesity due to decreased energy expenditure and lypolytic activity but show normal insulin sensitivity with hig adiponectin secretion.2005
Author(s)
Fan, W., Yanase, T., Nomura, M., Okabe, T., Goto, K., Sato, T., Kawano, H., Kato, S., Nawata H
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Journal Title
Diabetes 54(4)
Pages: 1000-1008
Description
「研究成果報告書概要(欧文)」より
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