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BDNF缺失导致食欲增大和肥胖症

来源:Journal of Neuroscience 2007-12-28 16:25

 生物谷报道:据美国的一个权威机构的调查显示,接近三分之一的美国人都是胖子,另外有三分之一则是体重超标。体重的过多增加由能量平衡的改变诱发。但是,是什么因子决定了人的饭量还不清楚。
 
来自美国Tufts大学医学院的Maribel Rios博士的研究组首次证实一种叫做脑衍生神经营养因子(BDNF, brain-derived neurotrophic factor,生物谷注)是介导成年小鼠饥饱的关键。他们的发现公布在12月26日的Journal of Neuroscience杂志上。
 
两个大脑食欲调控区域中的Bdnf基因被敲除的小鼠,其食量明显增加,并且比对照明显增重。研究人员表示,在这项研究前,他们已经知道BDNF或其受体在发育过程中的完全缺失会导致年轻小鼠食量过大和肥胖。但是,他们还不清楚是否BDNF是否在成年动物中也介导饥饱。
 
他们最新的发现表明,BDNF在VMH(ventromedial,丘脑腹内侧)和dorsomedial hypothalamus(DMH)中的合成是正常能量平衡的必须条件。另外,由于研究中使用的小鼠进行了基因改造,因此研究人员能够确定BDNF在成熟大脑中充当饥饱信号,该过程独立于发育大脑的功能。这个重要差异将可能帮助确定疾病机制和肥胖干扰治疗的关键时间。
 
研究人员表示,BDNF缺失小鼠的肥胖可能是由于过度消费卡路里导致。当食物量被限制时,突变小鼠能够恢复到正常体重范围。这意味着VMH和DMH中Bdnf基因的敲除不会影响能量的支出。
 
此前,在10月29日的《国际生物信息研究和应用杂志》上,来自美国犹他州杨伯翰大学的研究人员报道说,他们发现了基因在人体肥胖症中起主要作用的新证据。

新发现虽然是针对具有异常高肥胖症比例的现代北美印第安人的遗传基因的研究,但研究人员认为肥胖遗传基因有可能同样存在于其他人群中。之前的研究显示,生活在亚利桑那州和新墨西哥州索诺拉雷沙漠的北美印第安人具有较高的新陈代谢率。杨伯翰大学研究人员马克·罗和同事们对此现象进行了研究,并将重点放在研究对象体内被称为单核苷酸多态性(SNP)的线粒体DNA变异上。 

在研究中,他们先对200名患有肥胖症的北美印第安人的新陈代谢速度进行了测定,结果显示三分之二的患者其单核苷酸多态性影响了新陈代谢率。然后,研究人员又利用TreeSAAP遗传软件分析了这些SNP引起的生化变化,并在107种不同的哺乳动物中追踪了这些基因变异的进化选择过程。
 
研究组推测,较高的新陈代谢率可能具有进化优势。单核苷酸多态性(SNP)在北美印第安人的历史发展中帮助他们在苛刻的食物供应环境中生存下来,但在目前的卡路里摄入过高环境中,这种较高的新陈代谢率发挥了不适当的作用,可能导致他们出现高比例的肥胖者。

生物谷推荐英文原文:

The Journal of Neuroscience, December 26, 2007, 27(52):14265-14274; doi:10.1523/JNEUROSCI.3308-07.2007

Behavioral/Systems/Cognitive

Selective Deletion of Bdnf in the Ventromedial and Dorsomedial Hypothalamus of Adult Mice Results in Hyperphagic Behavior and Obesity

Thaddeus J. Unger,1 German A. Calderon,2 Leila C. Bradley,3 Miguel Sena-Esteves,4 and Maribel Rios2

Departments of 1Physiology and 2Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, 3Wyeth Pharmaceuticals, Cambridge, Massachusetts 02140, and 4Departments of Neurology and Neuroscience, Molecular Neurogenetics Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129

Correspondence should be addressed to Maribel Rios, Tufts University School of Medicine, Department of Neuroscience, 136 Harrison Avenue, Boston, MA 02111. Email: maribel.rios@tufts.edu

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are expressed in several hypothalamic and hindbrain nuclei involved in regulating energy homeostasis, developmentally and in the adult animal. Their depletion during the fetal or early postnatal periods when developmental processes are still ongoing elicits hyperphagic behavior and obesity in mice. Whether BDNF is a chief element in appetite control in the mature brain remains controversial. The required sources of this neurotrophin are also unknown. We show that glucose administration rapidly induced BDNF mRNA expression, mediated by Bdnf promoter 1, and TrkB transcription in the ventromedial hypothalamus (VMH) of adult mice, consistent with a role of this pathway in satiety. Using viral-mediated selective knock-down of BDNF in the VMH and dorsomedial hypothalamus (DMH) of adult mice, we were able to elucidate the physiological relevance of BDNF in energy balance regulation. Site-specific mutants exhibited hyperphagic behavior and obesity but normal energy expenditure. Furthermore, intracerebroventricular administration of BDNF triggered an immediate neuronal response in multiple hypothalamic nuclei in wild-type mice, suggesting that its anorexigenic actions involve short-term mechanisms. Locomotor, aggressive, and depressive-like behaviors, all of which are associated with neural circuits involving the VMH, were not altered in VMH/DMH-specific BDNF mutants. These findings demonstrate that BDNF is an integral component of central mechanisms mediating satiety in the adult mouse and, moreover, that its synthesis in the VMH and/or DMH is required for the suppression of appetite.

Key words: BDNF; VMH; DMH; satiety; obesity; adult

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