| 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)
大江 賢治 九州大学, 大学病院, 助手 (30419527)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥96,330,000 (Direct Cost: ¥74,100,000、Indirect Cost: ¥22,230,000)
Fiscal Year 2007: ¥27,690,000 (Direct Cost: ¥21,300,000、Indirect Cost: ¥6,390,000)
Fiscal Year 2006: ¥27,690,000 (Direct Cost: ¥21,300,000、Indirect Cost: ¥6,390,000)
Fiscal Year 2005: ¥40,950,000 (Direct Cost: ¥31,500,000、Indirect Cost: ¥9,450,000)
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| Keywords | androgen receptor / leptin / obesity / atherosclerosis / selective androgen receutor modulator / dehydroepiandrosterone / LOX-1 / 肥満X / SARM / STAT3 |
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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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