Gene expression in fat/skinny twin pairs

A couple of days ago I discussed the association of obesity with variants in the FTO gene in children of European and African ancestry. Continuing on the obesity theme is this intriguing study published this week in PLoS Medicine, which examines a small but potentially highly informative group of subjects: a set of 14 pairs of identical twins classed as "discordant for obesity", which means that one is substantially fatter than the other.

Discordant identical twin pairs are an endless source of fascination for researchers, who collect and categorise them like rare butterflies in vast twin repositories. In this study, the twins provided an opportunity to look at the factors that lead to obesity despite a shared childhood environment and nearly (see below) identical genomes. The researchers ran the twins through a panel of tests, including scans for body composition, screens for blood insulin levels, and extensive analyses of gene expression profiles in fat.

The two most interesting results: the fat twins had fewer mitochondria (the structures in our cells responsible for converting food into useful energy) in their fat, and also some clear differences in gene expression in their fat cells. The mitochondrial result is completely novel, and may indicate a derangement of energy metabolism in the fat cells of obese individuals - but it's unclear whether this represents a cause or an effect of obesity. The gene expression profiles show a range of differences, with the obese twins had higher levels of expression for some genes involved in inflammation, and lower levels for other pathways (particularly for mitochondrial genes involved in amino acid metabolism). Overall, these findings are intriguing rather than transformative, and it's going to be tough to untangle the chains of causation.

So, where are these differences coming from? If you'd asked me that a few months ago I'd have guessed that this variation was largely environmental in origin, with perhaps some stochastic epigenetic differences (chemical modifications of DNA that alter gene expression) accounting for the rest, but now I'm not so sure: a recent article in the American Journal of Human Genetics shows the extant to which even identical twins can differ at the genetic level due to mutations occurring during development or adult life. These mutations are not necessarily subtle, with one of the twins analysed in the study showing a whopping 1.6 million base pair deletion on chromosome 2 in 70-80% of his blood cells. (For more on this study, I'd recommend John Hawks and the NY Times.)

It seems unlikely that these mutations are responsible for most of the observable differences between typical pairs of identical twins - many of which you can instead blame on the psychological scars left by childhoods dressed in matching outfits - but they may well be enriched in highly discordant pairs such as the ones analysed in the obesity study. Unfortunately for the twin collectors, it's going to take much bigger cohorts than this to demonstrate that with any degree of confidence.

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Pietiläinen, K.H., Naukkarinen, J., Rissanen, A., Saharinen, J., Ellonen, P., Keränen, H., Suomalainen, A., Götz, A., Suortti, T., Yki-Järvinen, H., Orešič, M., Kaprio, J., Peltonen, L. (2008). Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity . PLoS Medicine, 5(3), e51. DOI: 10.1371/journal.pmed.0050051

Images from here and here.