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Lose weight with gene therapy

Monday, 12 January, 2009

Want to eat fatty food and tell your body to not bother storing that fat all over your body? Well, research recently published in the advanced online publication of  Nature Medicine has done just that, albeit in mice. They created knock-out mice, missing the gene Pla2g16, which codes for the enzyme adipocyte phospholipase A2. This enzyme, abbreviated to AdPLA, and other members of the PLA  (phospholipase A2) family, catalyse the first – and rate limiting – step in the production of eicosanoids, which are signalling molecules. As this enzyme was expressed in adipocytes (which are fat cells), the researchers hypothesised it would be involved in producing molecules that control adipose-specific processes, like lipolysis (fat breakdown).

It turns out they were right. Genetically obese (ob/ob) mice were found to be producing far more AdPLA and diabetic mice increased their AdPLA after receiving insulin. So, this molecules was sure to be involved in metabolising fat somehow.

The researchers made AdPLA-null mice, which lacked the gene to produce this enzyme. They fed these mouse a diet high in fat, and did the same to wild-type mice (which still had the gene). The two groups were not different in weight at weaning, but after 64 weeks of that diet, the AdPLA-null mice weighed an average of 39.1±0.2g in comparison to the average weight of 73.7±0.3g for wild-type mice. But, they didn’t eat any less (in terms of grams of food per gram of body weight). Further, the researchers knocked out the gene in a line of genetically obese mouse, and despite them eating more than any other mouse line, they were only slightly more overweight than wild-type mouse on an ordinary diet. And, the AdPLA mice weren’t exercising any more than the other mice either. A picture is given below:

Shows a genetically obese ob/ob mouse, and one with the same obese genes but with the AdPLA2 gene knocked out

A mouse with a genetic defiency of the appetite-supressor hormone leptin (left), and one with the same leptin-deficiency but with the AdPLA2 gene knocked out (right). From Jaworski et al, 2009

Further analysis revealed that this reduction in body mass was correlated with a reduction in the size of fat cells in AbPLA-null mice. This, in turn, was likely caused by the increased level of lipolysis and increased triacylglycerol production and turnover.  Therefore, the hypothesis is that AbPLA is involved in the regulation of lipolysis by catalysing a key step in the production of prostaglandins, and specifically PGE2. PGE2 has an anti-lipolytic, meaning it promotes fat to be stored rather than released. So, remove the enzyme that produces of PGE2, and the fat just isn’t stored.

In addition, the AbPLA-null mice were more insulin resistant, which makes sense. Insulin is responsible for stimulating the uptake and storage of food, so if mice are eating more and not gaining weight, they must be less sensitive to insulin. The study indicated AdPLA-null mice had 74% reduced insulin-stimulated glucose uptake in adipose tissue. In other words, they were eating lots of food, but it wasn’t being stored as fat. Where is it going? Researchers found the AdPLA-null mice had 37% increased oxidative metabolism, and therefore required more oxygen. This means that the fat cells are using the fat up, burning it rather than storing it. In addition, the researchers hypothesise that the free-fatty acids produced by the higher rate of lipolysis may not be significantly greater, as the fat cells aren’t taking up the fat, even before they get the chance to release it at the faster rate.

So, what does all this mean? The researchers hint at it:

Many questions remain regarding the effect of partial or total PLA2G16 gene ablation in humans

What questions? Well, for one, does this research mean that I can eat fatty foods and yet still not gain weight? I’d say it’s promising. Gene therapy seems a bit drastic at this early stage, so in the near future perhaps RNA interference, or a drug inhibiting this enzyme, will be a useful and reversible treatment for obesity. But, in the future, people will surely be tweaking their genes to ensure they remain at an optimum weight, regardless of how much more than the required intake of food is consumed. Bring on the deep-fried ice cream!

Reference: Jaworski et al, “AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency” Nature Medicine, AOP 11 January 2009 DOI: 10.1038/nm.1904

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