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Gene knockout prevents obesity in mice

14 September 2009
Appeared in BioNews 525

Mice that have been engineered to lack a gene called IKKE are protected from obesity, new research has found. IKKE, a normal immune system gene, appears to act as the main control centre for obesity in the laboratory mice and when it is successfully blocked the animals remained thin even when fed a diet high in fat. The researchers, from the University of Michigan, Ann Arbor, US, do not know whether IKKE is linked to obesity in humans but have speculated that, if it is, new treatments for Type 2 diabetes and obesity could be on the market within a decade. Details of the findings were published in the journal Cell.

IKKE is a gene involved in inflammation, and the American researchers were motivated to begin their investigation because Type 2 diabetes and obesity are both believed to be linked to low-level inflammation. They hypothesised that knocking out IKKE might break the link between the two conditions. To their surprise they found that blocking IKKE protected the mice against the worst metabolic consequences of a high-fat diet, including most of the associated weight gain.

Metabolic regulation differed between normal mice and those without IKKE when they were fed a normal diet (4.5 per cent fat), even although their body weights were similar. In particular, insulin levels were about 50 per cent higher in the knockout mice, but oxygen consumption (a measure of energy expenditure) remained similar. However, when fed a high-fat diet (45 per cent fat) oxygen consumption nearly doubled in the engineered mice but changed very little in the normal mice, which explains the much smaller weight gain they experienced. 'The mice burn more calories even though they aren't eating any less or exercising more', said Alan Saltiel, director of the Life Science Institute at the University of Michigan. 'They apparently keep the weight off on a diet loaded with fat by producing a little heat.'

Apart from keeping relatively slim, other benefits that the mice without IKKE enjoyed included lower cholesterol levels, and protection against type 2 diabetes and liver disease. But the story is far from a happy ending, as Saltiel pointed out that earlier findings have shown these mice are far more susceptible to lethal viral infections, maybe because of the role IKKE plays in the immune system. Nevertheless he remains positive: 'The fact that you can disrupt all the effects of a high-fat diet by deleting this one gene in mice is pretty interesting and surprising', he said. His team are now searching for a drug candidate that could stop the IKKE gene from functioning and he is certain that others will be doing the same.

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