Disabling a gene in specific mouse cells, researchers have prevented mice from becoming obese, even after the animals had been fed a high-fat diet.
The researchers blocked the activity of a gene in immune cells. Because these immune cells — called macrophages — are key inflammatory cells and because obesity is associated with chronic low-grade inflammation, the researchers believe that reducing inflammation may help regulate weight gain and obesity. The study is published in The Journal of Clinical Investigation.
When people are obese, they burn fewer calories than those who are not obese. The same is true for mice. But according to co-first author the researchers found that obese mice maintained the same level of calorie burning as mice that were not obese — after the research team deleted the ASXL2 gene in the macrophages of the obese mice and, in a second set of experiments, after they injected the animals with nanoparticles that interfere with the gene’s activity.
Mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted high-fat diet (HFD)-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression.
Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. Despite high-fat diets, the treated animals burned 45% more calories than their obese littermates with a functioning gene in macrophages.
White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts.
Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity.
Exactly why this prevented obesity in the mice isn’t clear. Co-first author said it appears to involve getting white fat cells — which store the fat that makes us obese — to behave more like brown fat cells — which help to burn stored fat. The strategy is a long way from becoming a therapy, but it has the potential to help obese people burn fat at rates similar to rates seen in lean people.
Obesity prevented in mice treated with gene-disabling nanoparticles
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