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By changing mouse genes to block a protein associated with obesity, researchers at the Kennedy Institute of Rheumatology, NDORMS have prevented fat from forming around the animals' internal organs, even when the animals eat an unhealthy diet. The study in Nature Medicine found that these genetically engineered mice also retained their sensitivity to insulin (normally blunted by obesity), despite gaining weight.

By changing mouse genes to block a protein associated with obesity, researchers at the Kennedy Institute of Rheumatology, NDORMS have prevented fat from forming around the animals' internal organs, even when the animals eat an unhealthy diet. The study in Nature Medicine found that these genetically engineered mice also retained their sensitivity to insulin (normally blunted by obesity), despite gaining weight.

Visceral fat deposits around internal organs in the stomach are particularly harmful: they are associated with insulin resistance, type-2 diabetes and heart disease. The study, conducted in close collaboration with researchers at the at the French Institute of Health and Medical research (INSERM) in Paris, shows that changing the pattern of fat deposition from around the stomach to under the skin starts a chain of events which result in insulin sensitivity being maintained, reducing the chances of type-2 diabetes.

Scientists already know that visceral fat attracts special M1-type macrophages (immune cells that attack infections and damaged cells). These M1-type macrophages produce harmful proteins that promote insulin resistance. 'We've previously found that a protein called interferon regulatory factor-5 (IRF-5) seems to push macrophages to change from a more 'peaceful', M2-type to the more aggressive M1-type', said Professor Irina Udalova at the Kennedy Institute, 'so we wondered if 'deleting' IRF-5 might have a beneficial effect'.

To test this idea, the two research teams fed the mice that were lacking the gene coding for IRF-5 with a healthy diet or a high-fat one. The mice with genetic changes were no different from standard lab mice when both the groups ate the healthy diet. Both groups of mice gained weight when they ate the high-fat diet. However, the mice with the altered gene piled on the fat under the skin, rather than around the internal organs in their stomach. The size of the fat cells in the stomach was also smaller in these mice, because there was more collagen (a 'scaffolding' protein that provides the structure for many parts of the body) deposits, holding the fat cells in.

'The mice without IRF-5 still got fat, but what was different was where they deposited this fat. We know that people who put on fat around their belly have a higher risk of developing obesity-related illnesses such as type-2 diabetes, compared to people who put on weight around their thighs. But we can't change the pattern of fat deposition in people, which we can now do in these mice. So this turned out to be an excellent way of testing if changing the pattern of fat deposition actually changes the factors that lead to type-2 diabetes', said Professor Udalova.

The researchers tested this idea by giving the mice a very sweet drink, containing glucose. They then tracked how quickly the glucose was broken down by insulin. Obesity can make the body less sensitive to insulin, which means that it takes longer for the glucose to disappear from the blood stream. This loss of sensitivity can eventually lead to type-2 diabetes. Despite being fatter, the mice without IRF-5 did better than the standard mice on this glucose challenge test.

 

You can read the full news article on the University of Oxford's website.

You can read the full paper, Irf5-deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity, in Nature Medicine.