| Co-Investigator(Kenkyū-buntansha) |
HARADA Kenji University of Tokyo Facoolty of Medicin Medical Staff, 医学部・附属病院, 医員
GOTODA Takanari University of Tokyo, Facoolty of Medicin Assistant Professor, 医学部・附属病院, 助手 (60322062)
SHIMANO Hitoshi University of Tsukuba Lecturer, 臨床医学系内科, 講師 (20251241)
OSUGA Jun-ichi University of Tokyo Facoolty of Medicin Medical Staff, 医学部・附属病院, 医員
山田 信博 東京大学, 医学部・附属病院, 助教授 (40200729)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2000: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1999: ¥10,700,000 (Direct Cost: ¥10,700,000)
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| Research Abstract |
Obesity is frequently associated with various coronary risk factors such as diabetes, hyperlipidemia and hypertension. Obesity is primarily caused by excessive accumulation of triacylglycerol (TG) in adipocytes, and sometimes by the increased number of adipocytes. In particular, TG in the adipocytes is hydrolyzed by an enzyme, hormone-sensitive lipase (HSL), suggesting that HSL plays a important role in the development of obesity. However, no genetic abnormalities of HSL have been found to be associated with either clinical obesity or hyperlipidemia, prompting us to hypothesize that there are multiple TG lipases in adipocytes. Furthermore, it is known that HSL is widely expressed throughout the body, particularly in testis, adrenal glands, brain, cardiac muscle, skeletal muscle, pancreatic b-cells. However, the precise functions of HSL in these organs remain unclear. To clarify the role of HSL in obesity, we have generated HSL knockout mice.
Exon 6 which encodes a central motif of the c
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atalytic site, GXSXG, has been replaced by neo cassette. Homologous recombination in ES cells produced mice lacking neutral cholesterol ester hydrolase (NCEH) activities in adipocytes and testes. HSL knockout mice exhibited male sterility due to oligospermia, Spermatogenesis may be disturbed in these mice. Even though NCEH activities were eliminated in adipocytes in both white adipose tissue (WAT) and brown adipose tissue (BAT), these adipocytes retained significant TG lipase activities which are distinct from HSL or from lipoprotein lipase (LPL). Body weight and weight of WAT were not increased in HSL knockout mice. However, individual adipocytes were enlarged by twice in diameter. These results suggest that there is heterogeneity in adipocyte populations in WAT.Consistent with the residual TG lipase activities in WAT, adipocytes isolated from WAT of HSL knockout mice showed an increase in FFA and glycerol release in response to isoprpterenol. From these results, we speculate that lipolysis is mediated by at least two distinct lipases, one is HSL and another is yet to be known. Less
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