Date Published: March 11, 2008
Publisher: Public Library of Science
Author(s): Kirsi H Pietiläinen, Jussi Naukkarinen, Aila Rissanen, Juha Saharinen, Pekka Ellonen, Heli Keränen, Anu Suomalainen, Alexandra Götz, Tapani Suortti, Hannele Yki-Järvinen, Matej Orešič, Jaakko Kaprio, Leena Peltonen, Leif C Groop
Abstract: BackgroundThe 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.Methods and FindingsWe 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/m2. 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.ConclusionsOur findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.
Partial Text: Adipose tissue is a key player in obesity-related metabolic dysfunctions, and is closely linked to other peripheral organs that control energy flux . To understand the pathogenesis of adipose tissue dysfunction at a molecular level, a global view of the networks and their interactions should be more informative than monitoring single-gene effects . Expression array studies on human adipose tissue have shown that the various inflammatory pathways are activated in obesity [3,4] and are down-regulated following weight loss . The major inflammatory cells in fat are macrophages of different subtypes [6,7], which scavenge adipocyte debris from necrotic cells . Paradoxically in obesity, macrophage-secreted factors may result in impaired adipogenesis  by inhibiting the expression of adipogenic transcription factors including peroxisome proliferator-activated receptor-gamma (PPARγ) . Impaired adipogenesis and defects in mitochondrial energy metabolism in subcutaneous adipose tissue have been suggested to shift lipid storage into ectopic insulin-sensitive tissues such as the liver, skeletal muscle, and pancreas, resulting in severe insulin resistance [11,12]. Induction of adipocyte differentiation  and mitochondrial biogenesis  in subcutaneous sites could reverse these abnormalities . However, molecular pathways related to aberrations in adipocyte differentiation in obesity remain unknown. Furthermore, although mitochondrial dysfunction has been previously identified in muscle in human obesity and type 2 diabetes [16–18] as well as in the adipocytes of obese rodents [19,20], direct evidence of possible defects in mitochondrial function in adipocytes in human obesity is lacking.
Our carefully phenotyped MZ twins most discordant for obesity represent an ideal model to explore the effects of acquired human obesity independent of genetic factors. By constructing networks of global transcript profiles in subcutaneous fat biopsies, we identified several fundamental pathways with high relevance for obesity and its related insulin resistance (Figure 3). Our data suggest that obesity that is already in its early stages in healthy young adults is characterized by marked inflammation of adipose tissue, significantly reduced mitochondrial DNA copy number, and disturbed mitochondrial energy metabolism—statistically most significantly, the decreased catabolism of insulin secretion–enhancing BCAAs. These impairments correlated with the critical clinical measures of obesity: liver fat accumulation, reduced whole-body insulin sensitivity, hyperinsulinemia, and hypoadiponectinemia.