Pietiläinen Kirsi H, Naukkarinen Jussi, Rissanen Aila, Saharinen Juha, Ellonen Pekka, Keränen Heli, Suomalainen Anu, Götz Alexandra, Suortti Tapani, Yki-Järvinen Hannele, Oresic Matej, Kaprio Jaakko, Peltonen Leena
Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
PLoS Med. 2008 Mar 11;5(3):e51. doi: 10.1371/journal.pmed.0050051.
The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.
We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean +/- standard deviation (SD) age 25.8 +/- 1.4 y and a body mass index (BMI) difference 5.2 +/- 1.8 kg/m(2). Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.
Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.
复杂性状的后天因素在人类中难以剖析。肥胖就是这样一种性状，其代谢和分子后果源自基因与环境的复杂相互作用。鉴于肥胖相关的大量发病率，深入了解同时发生的代谢变化具有相当重要的意义。本研究的目的是在相同遗传背景下研究这一重要的后天因素，并揭示肥胖诱导的生物途径变化。
我们采用了一种“克隆对照”的特殊研究设计，通过一个包含2453对年轻健康双胞胎的全国登记系统，识别出了肥胖程度不一致的罕见同卵双胞胎。共研究了14对双胞胎（8对男性，6对女性；均为白人），平均年龄±标准差（SD）为25.8±1.4岁，体重指数（BMI）差值为5.2±1.8 kg/m²。对皮下脂肪和外周血白细胞中线粒体DNA（mtDNA）的序列分析显示，双胞胎之间没有异常的异质性。然而，肥胖双胞胎的脂肪中mtDNA拷贝数减少了47%。此外，对脂肪组织转录谱的新途径分析显示，线粒体支链氨基酸（BCAA）分解代谢显著下调（p<0.0001）。与这一发现一致，肥胖男性双胞胎中胰岛素分泌增强的BCAAs血清水平升高（升高9%，p=0.025）。这些发现具有临床相关性，在男女两性中，脂肪中线粒体氨基酸代谢途径的异常与肝脏脂肪堆积、胰岛素抵抗和高胰岛素血症密切相关，这些都是这些健康年轻成年人后天肥胖的早期异常表现。
我们的研究结果强调了线粒体能量和氨基酸代谢在肥胖及胰岛素抵抗发展中的重要作用。
