Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity

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.

Causes and consequences of obesity: the contribution of recent twin studies

“…A novel finding of great interest in our obesity-discordant MZ pairs was the dramatic reduction of copies of mitochondrial DNA in the adipose tissue of the obese co-twin. 12 Although the sequence of mitochondrial sequence was identical between the MZ twins (no evidence of heteroplasmy), the copy number of mitochondrial DNA in the obese co-twin's adipose tissue was only 53% of that of the lean co-twin. This was also associated with a clear reduction in the pathway responsible for the mitochondrial catabolism of branched-chain amino acids (BCAAs) that act as insulin secretagogues.…”

“…Non-obese co-twins are set as 1.0, and the obese co-twins' values are the ratio of obese to non-obese co-twins' values. Data are derived from Pietilainen et al 5 ; Mustelin et al 10 ; Pietilainen et al 12 fS-insulin, fasting serum insulin; Ia, intra-abdominal; mtDNA, mitochondrial DNA; Sc fat, subcutaneous abdominal fat. *Po0.05, **Po0.01, ***Po0.001.…”

“…57 In fact, the single most upregulated transcript (5.9-fold upregulated) in the adipose tissue of the obese co-twin was an inflammatory cytokine called osteopontin (SPP1, aka OPN). 12 Osteopontin is secreted by the swelling adipocyte and recruits an increasing number of macrophages that in turn recruit more macrophages, by also secreting osteopontin themselves. The predominant change clearly observed in the global transcript profiles was an upregulation of several different proinflammatory pathways in the adipose tissue of the obese twin.…”

“…Previously unrecognized dimensions of the inflammatory pathways were upregulated, with involvement not only of macrophages, but antigen presentation via MHC class II molecules, activation of lymphocytes and of the complement system. 12 In addition to local inflammation of the adipose tissue and concomitant insulin resistance, circulating markers of inflammation could be observed: elevated C-reactive protein levels 9 as well as newly recognized proinflammatory lipid species were discovered in large-scale lipidomics studies. 11 The most proximal physiological mechanism responsible for the development of inflammation in the adipose tissue has remained elusive.…”

Microbiota conservation and BMI signatures in adult monozygotic twins

“…Furthermore, current literature putatively links a large number of human genes to variations in body mass index (BMI). Recruitment of MZ twins discordant for BMI in studies exploring human transcript profiles has revealed several potential obesity marker-genes (Naukkarinen et al, 2010) and potential (mitochondrial) pathways that are associated with major BMI increases (Pietilainen et al, 2008). However, the identified human genes account for a relatively small amount of the observed variance in energy homeostasis (Saris and Tarnopolsky, 2003;Heid et al, 2011).…”