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Monday, March 24, 2008

Obesity: It's all in Your Cells?

Yesterday I blogged about a remarkable Finnish twin study, in which the investigators went to the considerable trouble of finding monozygotic twin pairs who showed marked differences in body weight. The biggest predictor of weight gain in these genetically identical but weight-discordant co-twins was a markedly lower physical activity level, which in turn, declined even further as the obese co-twins packed on the pounds.

Assuming that this was not just a bunch of "lazy" co-twins, I wondered about what biological factors could possibly be causing these co-twins to be less physically activity. The answer to this question may lie in the results of another study by the same investigators in the same set of twins published in the open access journal PLoS Medicine.

In this study, Kirsi Pietiläinen and colleagues compared the genetic expression profiles in fat cells and macrophages between the obese and non-obese co-twins. Because, by design, the twins were genetically identical, they were able to normalise expression patterns for differences in genetic background, gender and age - thereby cutting through the considerable noise generally associated with expression studies.

In short, the authors found that the fat tissue from the obese co-twins showed a significant up-regulation of inflammatory pathways, significantly reduced mitochondrial DNA copy number, and disturbed mitochondrial energy metabolism—statistically most significantly, the decreased catabolism of branched-chain amino acids (BCAA). These impairments correlated with critical clinical measures of obesity including liver fat accumulation, reduced whole-body insulin sensitivity, hyperinsulinemia, hypoadiponectinemia and adipocyte hypertrophy.

In one individual, who the investigators were able to study before and after an additional weight gain of around 11 Kg over 3 years, mtDNA copy number was further reduced while serum BCAA concentrations and inflammatory activity increased even further.

Although the authors acknowledge that correlations do not prove causality, it is clear from the tone of their discussion that they believe that the metabolic derangements and low mtDNA copy count are a consequence of the obesity and are thus amenable to treatment by diet and exercise (the "politically correct" conclusion).

This is where I wonder if not the reverse may be true. I am no expert on mitochondrial biology, but I would assume that a key consequences of a reduction in mtDNA copy number is a decreased maximal capacity for oxidative phosphorylation, i.e., utilization of fat for energy production.

Assuming for a moment that these findings are also present in skeletal muscle, it would not be hard to imagine that these individuals are likely to find exercise more difficult and tiring than their co-twins with a normal mitochondrial population - less exercise means further weight gain and further decline in mitochondrial function - a nice little vicious cycle, if I ever saw one.

It is hard for me to image that in all 14 obese co-twins lack of physical activity alone was able to bring about the reduced mtDNA copy number, increased inflammation and reduced BCAA metabolism - somehow I find it easier to imagine that it was rather a malfunction in their mitochondria which significantly affected their ability to be (and enjoy being) physically active in the first place.

But of course, this is a chicken-or-egg question that cannot be resolved by the present study.

So the obvious questions now are: Can these co-twins be "rescued" by prescribing higher activity levels? How much activity will be needed to reverse these changes? And most importantly, will these co-twins stick with this prescription?

It's probably hard to enjoy exercise when there's a problem with your fuel cell.


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