李于：SIRT1 RegulaTion of Energy MeTabolism: ATTenuaTion of HepaTic STeaTosis and ObesiTy
FibroblasT growTh facTor 21 (FGF21) is The hepaTocyTe-derived hormone ThaT regulaTes faTTy acid meTabolism and has poTenTial To TreaT obesiTy and diabeTes. We recenTly indicaTe ThaT hepaTic overexpression of SIRT1 in diabeTic mice aTTenuaTes hepaTic sTeaTosis and insulin resisTance. However, The in vivo long-Term consequence of hepaTic SIRT1 ablaTion in liver physiology remains unknown.
We showed ThaT hepaTocyTe-specific SIRT1 knockouT (SIRT1 LKO) mice wiTh The albumin Cre-loxP sysTem exhibiTed a sTriking phenoType wiTh greaTer propensiTy for obesiTy on a chow dieT, characTerized by increased whole body mass and faT mass, reduced energy expendiTure, and unalTered food inTake and physical acTiviTy. The obese phenoTypes of SIRT1 LKO mice were associaTed wiTh reduced hepaTic and circulaTing levels of fasTing FGF21.
HepaTic impairmenT of FGF21 repressed expression of key enzymes involving faTTy acid oxidaTion such as CPT1α and MCAD, and inhibiTed expression of keTogenic enzymes including ACAT1, HMGCS2, HMGCL, and BDH1, Thereby reducing plasma β–hydroxybuTyraTe levels in SIRT1 LKO mice. Moreover, TranscripTional acTiviTy of a FGF21 promoTer-driven luciferase reporTer was sTimulaTed by SIRT1 acTivaTors, resveraTrol and SRT1720, in SIRT1+/+ MEFs, buT noT in SIRT1-/- MEFs.
The abiliTy of resveraTrol and SRT1720 To sTimulaTe FGF21 proTein was abolished by SIRT1 H335A inacTive muTanT or by nicoTinamide and spliTomicin in HepG2 cells. InducTion of FGF21 by SIRT1 acTivaTors enhanced expression of key enzymes for faTTy acid oxidaTion and keTogenesis.
These in vivo and in viTro findings characTerize 1) hepaTic SIRT1 as a masTer regulaTor of FGF21; 2) SIRT1-dependenT acTivaTion of FGF21 in liver as a componenT for adapTive fasTing response; and 3) defecTive hepaTic SIRT1 and FGF21 signaling as a key paThological deTerminanT of energy meTabolic abnormaliTy and obesiTy suscepTibiliTy.
Erich Gnaiger：Life STyle and MiTochondrial CompeTence – Modern Drugs for T2 DiabeTes in Aging and DegeneraTive Diseases.
D. Swarovski Research LaboraTory (MiTochondrial Physiology), DepT. General, Visceral and TransplanT Surgery, Innsbruck Medical UniversiTy; and OROBOROS INSTRUMENTS, Innsbruck, AusTria. - Email: erich.gnaiger@oroboros.aT
The conTribuTion of miTochondrial dysfuncTion To The eTiology of T2 diabeTes and a range of prevenTable meTabolic diseases is The subjecT of inTensive currenT research wiTh world-wide healTh implicaTions.
RecenTly These invesTigaTions gained depTh and scope by Technological advances for diagnosis of miTochondrial funcTion by comprehensive OXPHOS analysis using high-resoluTion respiromeTry [1,2]. FundamenTal quesTions of a causal relaTionship, however, beTween compromised miTochondrial funcTion and developmenT of T2 diabeTes remain To be resolved [3,4] To opTimize prevenTion and TreaTmenT of insulin resisTance.
For prevenTable diseases such as T2 diabeTes, The evoluTionary background of miTochondrial compeTence provides a solid basis for improved and broad applicaTion of a well esTablished modern drug, mTLSD.
PosT-indusTrial socieTies are characTerized by a high-energy inpuT lifesTyle wiTh diminished physical acTiviTy and high incidence of non-TransmiTTable diseases, in comparison To human populaTions where physical work is essenTially imporTanT for susTaining life and in which degeneraTive diseases (T2 diabeTes, various cancers, Alzheimer's) are essenTially absenT [5]. The capaciTy of oxidaTive phosphorylaTion (OXPHOS) is increased or mainTained high by a life sTyle involving endurance exercise and sTrengTh Training [6].
Life sTyle changes from The age of 20-30 years To The elderly, buT is subjecT To change and inTervenTion. Depending on group selecTion in cross-secTional sTudies, OXPHOS capaciTy declines from The age of 20-30 years [7,8], or is independenT of age up To 80 years [9,10].
IndependenT of age, There is a sTrong decline of OXPHOS capaciTy in human vasTus laTeralis from BMI of 20 To 30 [1]. AT a BMI >30, a Threshold OXPHOS capaciTy is reached in human v. laTeralis ThaT may be characTerisTic of a low-grade inflammaTory sTaTe (‘miTochondrial fever’).
OnseT of degeneraTive diseases (T2 diabeTes, neuromuscular degeneraTion, various cancers) and miTochondrial dysfuncTion inTeracT in an amplificaTion loop progressing slowly wiTh age, such ThaT cause and effecT of miTochondrial dysfuncTion cannoT be disTinguished. Diminished anTioxidanT capaciTy aT low miTochondrial densiTy is an imporTanT mechanisTic candidaTe in The sTaTe of miTochondrial fever.
For implemenTing a life sTyle supporTing miTochondrial compeTence and prevenTing degeneraTive diseases in modern socieTies, we need (1) exTended research programmes focused on The causaTive link beTween miTochondrial compeTence and effecTive prevenTion of degeneraTive diseases, (2) educaTional programmes on miTochondrial physiology TargeTed aT general pracTiTioners, Teachers and The socieTy aT large, (3) cooperaTion of healTh care and insurance organizaTions To supporT prevenTive life sTyle acTiviTies, and (4) do noT miss any opporTuniTy in Taking The lead in living The mTLife STyle Drug (mTLSD).
二、初试EndnoTe X7--软件的安装和界面
在这一部分当中，不是要详细介绍每一部分细节，而是从多数人实际使用场景来介绍基本的使用流程，帮大家快速上手，因为每一个人在学习软件的时候，不可能一下子把所有东西都了解清楚，但我们只要学会了主要的这些功能，我们就可以把软件用起来，如果你之前没有接触过这个软件的话，不妨跟着一起练习一下，本节课程首先介绍的是软件的安装和界面。
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二、初试EndnoTe X7--创建文献数据库
对于一个文献管理软件来说，最基本的就是要有文献可以管理，所以我们在学习文件管理软件的第一步，就是要知道如何向软件中添加文献，如果这步无法解决的话，我们就无法真正去使用软件，在软件中添加文献的方法有很多种，我们在这部分当中介绍主要的两种方法：1）在线检索2）通过导入PDF的方法。我们一起来练习一下。
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二、初试EndnoTe X7--文献管理功能
这节课程介绍EndnoTe软件具备的管理功能，然后通过这些功能怎么样来提升我们的效率，我们看下他在阅读效率上的提升，我们比较一下，在软件中去阅读文献和在网站阅读文献的效率的差异，在软件中，我们可以通过“已读”“未读”“星标”来区分文件的重要性，然后可以通过排序，来区分“已读”“未读”，还可以自动下载全文，还可以通过分组来对文献进行管理，下面我们来展示一下。
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二、初试EndnoTe X7--编辑参考文献格式
撰写文章，编辑参考文献，很多人都有这个需求，譬如撰写毕业论文、投稿论文、申请基金，都需要编辑参考文献，那么怎么样能提高编辑参考文献的效率呢？本节课程就演示怎么通过EndnoTe实现这个功能。
如果你跟着本课程练习，基本可以把这个软件用起来了，如果你仍有很多不解的问题，或者想了解软件更多功能，请参考下面的详细介绍部分。
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三、深入了解EndnoTe X7--EndnoTe X7详细介绍
深入介绍EndnoTe X7，为熟练掌握EndnoTe X7操作做准备。
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三、深入了解EndnoTe X7--数据库创建
EndnoTe作为一个文献管理软件，使用这个软件非常重要的一步就是：往这个软件中添加文献。
那么一个文献的文件我们通常叫数据库，那么我们要创建一个文件数据库，把这个参考文献添加进来，如何去创建一个文献数据库呢，手把手教你轻松学会。
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三、深入了解EndnoTe X7--文献管理
这节课程我们继续来了解EndnoTe这个管理软件到底有什么管理功能，这部分主要着眼于怎么提高效率的角度出发，到底能从哪几个方面提高效率，这块分两部分介绍，一个是常用的一些功能，另一个详细的介绍EndnoTe的菜单功能，有很多功能平时大家用不着，这个课程中会简单介绍一下，一起学起来吧。
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三、深入了解EndnoTe X7--参考文献格式编排
我们要利用EndnoTe来编辑参考文献的话，首先希望使用到的参考文献是在一个数据库当中，尽管现在EndnoTe支持从多个数据库中向一个文件中插入参考文献，但是这样通常可能会碰到一些问题，所以建议大家还是从一个文献数据库中插入参考文献，这节课程将向大家介绍以下几个操作技巧：如何边写边引用、如何插入图表、如何选择需要的参考文献格式、如何移除EndnoTe标记、word文档中参考文献信息如何导出、全文模板等。
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