This is the third and final post in my series on the Fto gene. The appearance of a new an exciting paper will, of course, increase the probability of me emitting another Fto related post, but this is it for the time being. Fto is an exciting gene, however, so it likely won’t be long before yet another exciting paper emerges.
So far we have learned of evidence for the association between common Fto variants in humans and obesity. We have also had a glimpse of how Fto functions in the regulation of appetite and obesity in rats and mice. Having support for its role in human obesity and evidence that it is active during relevant situations in rodents, it seems the next step is to actively inhibit Fto in rodents and see what happens when it’s not there. Basic science often follows this sortof progression.
Here, Fischer and company generate a knockout mouse that lacks a functioning Fto gene. Knockout mice are genetically engineered in such a way that a particular gene (or genomic region) is removed or otherwise rendered non-functional. When researchers are interested in the function of a particular gene, it becomes useful to study animals that are missing that gene and compare them to wild type animals in which that gene is working normally.
The first and most obvious result of this experiment is that Fto deficient mice are born smaller than their wild type counterparts, and they remain significantly smaller throughout their lifespan. Knockouts were also less fat – males and females carried 60% and 23% less fat than wild types respectively. Curiously, knockouts did not eat less than wild types. Relative to their body weight, they actually ate more than wild types, yet failed to grow or gain as much weight. Knockouts were also protected to some extent from diet-induced obesity, as they gained significantly less weight than wild types when given access to a high-fat diet for 12 weeks.
Fat plays an obvious role in the storage of energy, but it also functions as a major endocrine organ. Adipokines such as leptin and adiponectin are hormones secreted by fat that, among other things, inform the brain about energy balance and modulate appetite accordingly. Leptin is an anorexigenic hormone that is positively correlated with fat mass, so more fat should equal more leptin. Adiponectin is inversely correlated with fat mass. Since Fto knockout mice have less fat than wild type mice, we would expect them to have lower levels of leptin, and higher levels of adiponectin, and indeed that is exactly what was seen.
So we noted earlier that Fto knockouts eat more, but gain less weight. To understand why this happens, the researchers monitored their locomotor behavior and metabolic rate. It seems that Fto knockouts have significantly greater oxygen consumption and carbon dioxide production, which suggests a higher level of energy expenditure. Moreover, these mice had greater levels of locomotor activity, suggesting that they are burning all that energy by moving around a lot. Interestingly, human variants of Fto associated with obesity result in increased food intake with no corresponding increase in metabolic rate. Perhaps this suggests that Fto is involved in that aspect of energy balance regulation. Knockout mice showed increased circulating adrenaline levels, suggesting that it may play a role in their increased activity levels and energy expenditure.
So the question becomes whether Fto in humans is playing a similar role to what we saw here in mice. It is important to note that the knockout model is not perfect by any means. A very tiny mutation in human Fto exerts a noticeable effect on obesity in humans, which is quite a bit different from the wholesale removal of the gene as seen in this study. The role of this type of study is not, of course, to attempt to replicate the human condition, but rather to inform future research by rendering a number of the gene’s most important functions more visible. If these effects are seen in knockouts, perhaps they are present, though subtler in human cases.
It is probably too easy to interpret data related to Fto in both humans and animals to suggest that possessing a certain version of this gene dooms one to obesity. It turns out, however, that lifestyle has a marked influence on phenotype. Individuals possessing the risk allele of Fto can blunt its effect through exercise (Rampersaud et al., 2008). While our individual genetic endowments remain set throughout the lifespan, we can exert significant control over how these genes are expressed by manipulating our environments.
Fischer, J., Koch, L., Emmerling, C., Vierkotten, J., Peters, T., Brüning, J., & Rüther, U. (2009). Inactivation of the Fto gene protects from obesity Nature, 458 (7240), 894-898 DOI: 10.1038/nature07848
Rampersaud, E., Mitchell, B. D., Pollin, T. I., Fu, M., Shen, H., O’Connell, J. R., Ducharme, J. L., et al. (2008). Physical activity and the association of common FTO gene variants with body mass index and obesity. Archives of Internal Medicine, 168(16), 1791-1797. doi:10.1001/archinte.168.16.1791