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【medical-news】敲除小鼠一种关键蛋白意外增强了胰岛素敏感性

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http://www.sciencedaily.com/releases/2011/11/111110125727.htm
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ScienceDaily (Nov. 10, 2011) — By knocking out a key regulatory protein, scientists at the University of California, San Diego School of Medicine and the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland dramatically boosted insulin sensitivity in lab mice, an achievement that opens a new door for drug development and the treatment of diabetes.

The research, published in the November 11 issue of the journal Cell, reveals a new and previously unsuspected role for nuclear receptor corepressor (NCoR), a transcriptional coregulatory protein found in a wide variety of cells.

"Different transcription factors stimulate genes, turning them on and off, by bringing in co-activators or co-repressors," said Jerrold M. Olefsky, MD, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego and senior author of the paper. "All transcriptional biology is a balance of these co-activators and co-repressors."

Olefsky and colleagues focused their attention on NCoR, which was known to be a major co-repressor of Peroxisome Proliferator-Activated Receptor gamma or PPAR-gamma, a ubiquitous protein that regulates fatty acid storage and glucose metabolism, but which also appeared to act on other receptors as well.

"It seemed to be a general purpose co-repressor," said Olefsky. "It's unusual for one protein to do so many things. It's not very efficient and you don't see it too much in biology."

The scientists created a knock-out mouse model whose adipocytes or fat cells lacked NCoR. Though bred to be obese and prone to diabetes, Olefsky said the glucose tolerance improved in the NCoR knock-out mice. Moreover, they displayed enhanced insulin sensitivity in liver, muscle and fat, and decreased systemic inflammation. Resistance to insulin, a hormone central to regulating carbohydrate and fat metabolism, is a hallmark of diabetes, as is chronic inflammation.

"When NCoR was deleted, insulin sensitivity in the whole animal increased dramatically compared to normal obese mice, which remained insulin resistant. The sensitivity occurred not just in adipocytes, but in all cells," said Olefsky. "With NCoR knocked out of adipocytes, PPAR-gamma becomes active. This produces a robust increase in systemic insulin sensitivity."

Phosphorylation is a biochemical process in which a phosphate group is added to a protein or other organic molecule, activating or deactivating many protein enzymes. It turns out that NCoR facilitates phosphorylation of PPAR-gamma, so that without NCoR, the receptor remains unphosphorylated and active.

In related work also published in the same issue of Cell, EPFL scientists found that knocking out NCoR in muscle cells produced a surprising effect. It did not repress PPAR-gamma, but rather generated a different phenotype or set of results.

"In adipocytes, NCoR repressed PPAR-gamma, but in other cells, it appears to repress other transcription factors," Olefsky said. "That's a new principle: A repressor that's found in many cells, but performs a specific, different function depending on the cell type."

Though NCoR's role as a major co-repressor was known, it was considered a poor drug target because inhibiting it could cause unwanted de-repression in some cell types, producing adverse side effects. Olefsky said the newly discovered specificity of NCoR revitalizes the idea that NCoR may be an excellent drug target for type 2 diabetes and other insulin resistant diseases.

"If researchers can make a drug that's tissue-specific, repressing NCoR could be a powerful way to boost insulin sensitivity. It's doable. Already, we can create drugs that specifically target fat and liver cells. That might be good enough to produce a system-wide benefit."

Co-authors of the study are Pingping Li, WuQiang Fan, Jianfeng Xu, Min Lu, Dorothy D. Sears, Saswata Talukdar, DaYoung Oh, Ai Chen, Gautam Bandyopadhyay, Jachelle M. Ofrecio and Sarah Nalbandian of the Division of Endocrinology and Metabolism, Department of Medicine, UC San Diego; Hiroyasu Yamamoto and Johan Auwerx of the Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Federale de Lausanne and Miriam Scadeng, Department of Radiology, UC San Diego.

Funding for this study came, in part, from the National Institutes of Health, the EU Ideas Program, the Swiss National Science Foundation and the Eunice Kennedy Shriver National Institute of Child Health & Human Development as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research.

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2011-11-15 23:52 浏览 : 703 回复 : 4

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2011-11-16 08:36

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ScienceDaily (Nov. 10, 2011) — Byknocking out a key regulatory protein, scientists at the University ofCalifornia, San Diego School of Medicine and the Ecole Polytechnique Federalede Lausanne (EPFL) in Switzerland dramatically boosted insulin sensitivity inlab mice, an achievement that opens a new door for drug development and thetreatment of diabetes.

每日科学(2011年11月10日)-通过，加州大学圣地亚哥分校医学院和瑞士洛桑联邦理工学院(EPFL)的科学家发现，通过敲除关键的调节蛋白，能够显著提高小鼠对胰岛素的敏感性，这一成就为新药物开发和糖尿病的治疗打开了一扇门。

The research, published in the November11 issue of the journal Cell, reveals a new and previously unsuspected role fornuclear receptor corepressor (NCoR), a transcriptional coregulatory proteinfound in a wide variety of cells.

这项研究发表在细胞11月11日刊上，揭示了核受体辅阻遏物(NCoR)，一种在多种细胞中存在的转录辅调节蛋白的新作用。

"Different transcription factorsstimulate genes, turning them on and off, by bringing in co-activators orco-repressors," said Jerrold M. Olefsky, MD, associate dean for ScientificAffairs and Distinguished Professor of Medicine at UC San Diego and seniorauthor of the paper. "All transcriptional biology is a balance of theseco-activators and co-repressors."

科学事务副院长，加州大学圣地亚哥分校医学院特聘教授和资深作者，Jerrold M. Olefsky医学博士说：“不同的转录因子通过共同激活或共同??阻遏刺激基因打开或关闭”。“所有的转录生物学是共同激活或共同??阻遏的平衡。”

Olefsky and colleagues focused theirattention on NCoR, which was known to be a major co-repressor of PeroxisomeProliferator-Activated Receptor gamma or PPAR-gamma, a ubiquitous protein thatregulates fatty acid storage and glucose metabolism, but which also appeared toact on other receptors as well.

Olefsky和同事的注意力集中在核受体辅阻遏物，被称为是主要的过氧化物酶体增生物激活受体γ或PPAR -γ辅抑制物，同时也是一个无处不在的蛋白，能够调节脂肪酸的存储和糖代谢，但也作用于其他受体。

"It seemed to be a general purposeco-repressor," said Olefsky. "It's unusual for one protein to do somany things. It's not very efficient and you don't see it too much inbiology."

Olefsky说：“它似乎是一个通用的辅抑制物”。“它是一种特别的蛋白质，不能做很多事情，不是很高效，你在生物学上很少看到。”

The scientists created a knock-outmouse model whose adipocytes or fat cells lacked NCoR. Though bred to be obeseand prone to diabetes, Olefsky said the glucose tolerance improved in the NCoRknock-out mice. Moreover, they displayed enhanced insulin sensitivity in liver,muscle and fat, and decreased systemic inflammation. Resistance to insulin, ahormone central to regulating carbohydrate and fat metabolism, is a hallmark ofdiabetes, as is chronic inflammation.

科学家们建造了敲除脂肪细胞或脂肪细胞缺乏核受体辅阻遏物的小鼠模型。Olefsky说，虽然引起肥胖和容易患糖尿病，核受体辅阻遏物基因敲除小鼠的葡萄糖耐受性得到改善。此外，在肝脏，肌肉和脂肪组织显示胰岛素敏感性增强，并减少全身性炎症反应。调节碳水化合物和脂肪的代谢中枢性激素-胰岛素抵抗，调节，是糖尿病的标志也是慢性炎症。

"When NCoR was deleted, insulinsensitivity in the whole animal increased dramatically compared to normal obesemice, which remained insulin resistant. The sensitivity occurred not just inadipocytes, but in all cells," said Olefsky. "With NCoR knocked outof adipocytes, PPAR-gamma becomes active. This produces a robust increase insystemic insulin sensitivity."

Olefsky说：“胰岛素抵抗的正常肥胖小鼠相比，当核受体辅阻遏物被敲除，所有动物胰岛素敏感性显著增加。不仅发生在脂肪细胞，其他所有细胞中敏感性都增加”。 “脂肪细胞核受体辅阻遏物敲除，PPAR -γ变得活跃，这将引起全身胰岛素敏感性增强”。

Phosphorylation is a biochemicalprocess in which a phosphate group is added to a protein or other organicmolecule, activating or deactivating many protein enzymes. It turns out thatNCoR facilitates phosphorylation of PPAR-gamma, so that without NCoR, thereceptor remains unphosphorylated and active.

磷酸化是一个生化过程，其中磷酸基团加成到蛋白或其它有机分子中，激活或失活一些蛋白酶。核受体辅阻遏物促进PPAR -γ的磷酸化，没有核受体辅阻遏物作用，受体处于未磷酸化状态而显示活性。

In related work also published in thesame issue of Cell, EPFL scientists found that knocking out NCoR in musclecells produced a surprising effect. It did not repress PPAR-gamma, but rathergenerated a different phenotype or set of results.

洛桑联邦理工学院的科学家发现，肌肉细胞敲除核受体辅阻遏物产生了惊人的效果，相关工作发表在同一期细胞杂志上。没有抑制PPAR -γ，而是产生一个不同的表型或结果集。

"In adipocytes, NCoR repressedPPAR-gamma, but in other cells, it appears to repress other transcriptionfactors," Olefsky said. "That's a new principle: A repressor that'sfound in many cells, but performs a specific, different function depending onthe cell type."

Olefsky说：“在脂肪细胞中，核受体辅阻遏物压抑PPAR -γ，但在其他细胞中，它抑制其他转录因子。” “这是一个新的原理：在许多细胞中发现的一个抑制物，表现出特殊的，不同的功能由细胞类型而定。”

Though NCoR's role as a majorco-repressor was known, it was considered a poor drug target because inhibitingit could cause unwanted de-repression in some cell types, producing adverseside effects. Olefsky said the newly discovered specificity of NCoR revitalizesthe idea that NCoR may be an excellent drug target for type 2 diabetes andother insulin resistant diseases.

虽然核受体辅阻遏物被认为是主要的辅抑制物，但它被认为不是好的药物靶标，因为抑制它可能会导致某些类型的细胞不必要的脱抑制作用，产生不良的副作用。 Olefsky说，新发现的特异性的核受体辅阻遏物复活了核受体辅阻遏物作为优良的药物靶点的想法，可作用于II型糖尿病和其他胰岛素抵抗疾病。

"If researchers can make a drugthat's tissue-specific, repressing NCoR could be a powerful way to boostinsulin sensitivity. It's doable. Already, we can create drugs thatspecifically target fat and liver cells. That might be good enough to produce asystem-wide benefit."

“如果研究员可以研制出组织特异性药物，抑制核受体辅阻遏物可能是一个有效的方式增加胰岛素的敏感性。这是可行的。我们已经能够研制靶向性脂肪和肝细胞的药物。这可能使系统范围广泛受益。

Co-authors of the study are PingpingLi, WuQiang Fan, Jianfeng Xu, Min Lu, Dorothy D. Sears, Saswata Talukdar,DaYoung Oh, Ai Chen, Gautam Bandyopadhyay, Jachelle M. Ofrecio and SarahNalbandian of the Division of Endocrinology and Metabolism, Department ofMedicine, UC San Diego; Hiroyasu Yamamoto and Johan Auwerx of the Laboratory ofIntegrative and Systems Physiology, Ecole Polytechnique Federale de Lausanneand Miriam Scadeng, Department of Radiology, UC San Diego.

这项研究的共同作者有加州大学圣地亚哥分校内分泌和代谢科医学院的Pingping Li, WuQiang Fan, Jianfeng Xu, Min Lu, Dorothy D. Sears,Saswata Talukdar, DaYoung Oh, Ai Chen, Gautam Bandyopadhyay, Jachelle M.Ofrecio和Sarah Nalbandian;综合和系统生理学实验室的Hiroyasu Yamamoto和Johan Auwerx，洛桑联邦理工学院和加州大学圣地亚哥分校放射科Miriam Scadeng。

Funding for this study came, in part,from the National Institutes of Health, the EU Ideas Program, the SwissNational Science Foundation and the Eunice Kennedy Shriver National Instituteof Child Health & Human Development as part of the specialized CooperativeCenters Program in Reproduction and Infertility Research.

本研究的经费来自国家卫生研究院，欧盟创意计划，瑞士国家科学基金会和尤尼斯肯尼施莱佛国立儿童健康与人类发展专业合作中心项目生殖和不孕不育研究。

2011-11-17 22:07

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每日科学(2011年11月10日)-通过，加州大学圣地亚哥分校医学院和瑞士洛桑联邦理工学院(EPFL)的科学家发现，通过敲除关键的调节蛋白，能够显著提高小鼠对胰岛素的敏感性，这一成就为新药物开发和糖尿病的治疗打开了一扇门。

这项研究发表在细胞11月11日刊上，揭示了核受体辅阻遏物(NCoR)，一种在多种细胞中存在的转录辅调节蛋白的新作用。

科学事务副院长，加州大学圣地亚哥分校医学院特聘教授和资深作者，Jerrold M. Olefsky医学博士说：“不同的转录因子通过共同激活或共同??阻遏刺激基因打开或关闭”。“所有的转录生物学是共同激活或共同??阻遏的平衡。”

Olefsky和同事的注意力集中在核受体辅阻遏物，被称为是主要的过氧化物酶体增生物激活受体γ或PPAR -γ辅抑制物，同时也是一个无处不在的蛋白，能够调节脂肪酸的存储和糖代谢，但也作用于其他受体。

Olefsky说：“它似乎是一个通用的辅抑制物”。“它是一种特别的蛋白质，不能做很多事情，不是很高效，你在生物学上很少看到。”

科学家们建造了敲除脂肪细胞或脂肪细胞缺乏核受体辅阻遏物的小鼠模型。Olefsky说，虽然引起肥胖和容易患糖尿病，核受体辅阻遏物基因敲除小鼠的葡萄糖耐受性得到改善。此外，在肝脏，肌肉和脂肪组织显示胰岛素敏感性增强，并减少全身性炎症反应。调节碳水化合物和脂肪的代谢中枢性激素-胰岛素抵抗，调节，是糖尿病的标志也是慢性炎症。

Olefsky说：“胰岛素抵抗的正常肥胖小鼠相比，当核受体辅阻遏物被敲除，所有动物胰岛素敏感性显著增加。不仅发生在脂肪细胞，其他所有细胞中敏感性都增加”。 “脂肪细胞核受体辅阻遏物敲除，PPAR -γ变得活跃，这将引起全身胰岛素敏感性增强”。

磷酸化是一个生化过程，其中磷酸基团加成到蛋白或其它有机分子中，激活或失活一些蛋白酶。核受体辅阻遏物促进PPAR -γ的磷酸化，没有核受体辅阻遏物作用，受体处于未磷酸化状态而显示活性。

洛桑联邦理工学院的科学家发现，肌肉细胞敲除核受体辅阻遏物产生了惊人的效果，相关工作发表在同一期细胞杂志上。没有抑制PPAR -γ，而是产生一个不同的表型或结果集。

Olefsky说：“在脂肪细胞中，核受体辅阻遏物压抑PPAR -γ，但在其他细胞中，它抑制其他转录因子。” “这是一个新的原理：在许多细胞中发现的一个抑制物，表现出特殊的，不同的功能由细胞类型而定。”

虽然核受体辅阻遏物被认为是主要的辅抑制物，但它被认为不是好的药物靶标，因为抑制它可能会导致某些类型的细胞不必要的脱抑制作用，产生不良的副作用。 Olefsky说，新发现的特异性的核受体辅阻遏物复活了核受体辅阻遏物作为优良的药物靶点的想法，可作用于II型糖尿病和其他胰岛素抵抗疾病。

“如果研究员可以研制出组织特异性药物，抑制核受体辅阻遏物可能是一个有效的方式增加胰岛素的敏感性。这是可行的。我们已经能够研制靶向性脂肪和肝细胞的药物。这可能使系统范围广泛受益。

这项研究的共同作者有加州大学圣地亚哥分校内分泌和代谢科医学院的Pingping Li, WuQiang Fan, Jianfeng Xu, Min Lu, Dorothy D. Sears,Saswata Talukdar, DaYoung Oh, Ai Chen, Gautam Bandyopadhyay, Jachelle M.Ofrecio和Sarah Nalbandian;综合和系统生理学实验室的Hiroyasu Yamamoto和Johan Auwerx，洛桑联邦理工学院和加州大学圣地亚哥分校放射科Miriam Scadeng。

本研究的经费来自国家卫生研究院，欧盟创意计划，瑞士国家科学基金会和尤尼斯肯尼施莱佛国立儿童健康与人类发展专业合作中心项目生殖和不孕不育研究。

2011-11-17 22:08

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