Adipose tissue inflammation affects obesity-related diabetes
Type 2 diabetes is known to be linked to obesity and inactivity, but the impact of lifestyle and diet is moderated by genetic factors and not all obese people develop the disease or comorbidities, such as organ dysfunction. Changes to the epigenome associated with inflammation of the adipose tissue, which stores energy as body fat, could help explain why some obese people become diabetic while others do not. “We believe that part of the [body’s] response to surplus energy from junk food is written on the epigenome of the fat cells,” explains EpiFAT project coordinator Nicolas Venteclef, research director at France’s National Institute of Health and Medical Research (Inserm) in Paris. The EpiFAT project was funded by the European Research Council. “Over the genome is the epigenome which can respond to environmental factors. Because the epigenome is sensitive to energy surplus from overeating, the adipose tissue responds in an ‘unhealthy’ way, favouring type 2 diabetes or comorbidities,” he says.
Link to adipose tissue inflammation
“There are two kinds of obesity. What we call ‘healthy’ obesity – marked by low inflammatory status of the adipose tissue, and another type of obesity with very high inflammation and systemic events,” Venteclef explains. “With massive inflammation in the adipose tissue, we cannot properly regulate the glucose level in the blood. Because the main function of adipose tissue is to store the lipids and glucose in the tissue, it leads to an increase in the blood glucose level,” he notes. “We clearly demonstrated that in type 2 diabetes with visceral obesity and adipose tissue inflammation, patients are prone to specific complications, particularly liver steatosis and cardiovascular events.”
Epigenetic modifiers
Certain epigenome mechanisms have the potential to regulate such inflammatory processes and may also activate immune cells in adipose tissue. One project breakthrough was identifying two epigenetic modifiers involved in controlling adipose tissue inflammation and which can help avoid fat accumulating in parts of the body. During the first three years of the six-year project, mapping the epigenome in rodents and analysing how inflamed adipose tissue can affect rodent health, the team showed these modifiers had an impact on adipose tissue expansion and growth. “Unexpectedly, we realised that one of the epigenetic modifiers was very specific in avoiding accumulation of visceral (belly) fat. Instead, it accumulates as subcutaneous fat. This partly protects against disease, because we know that subcutaneous fat is not as pathological for diabetes as visceral fat,” Venteclef explains. “We do not understand how it works, but it is important to know, because if we target this modifier, we can at least change the way fat accumulates,” he says, adding this work will continue under the follow-on INTERCEPT-T2D project.
Translation to humans
The second half of the EpiFAT project sought to translate the rodent findings to humans, using human adipose tissue biopsies from thousands of type 2 diabetes patients. The team devised novel methods to analyse human adipose tissue, including flow cytometry and transcriptome analysis, to characterise the systemic and the tissue immune response. The early identification of diabetic patients with high inflammation is important so that anti-inflammatory drugs could be prescribed to avoid complications and help control the disease, he adds. The individual’s metabolism and immune system also has an effect. “We understand why some people are more sensitive to energy surplus or a high-calorie diet – it’s because they may have trained immune cells in their body fat that are sensitive to energy metabolism,” Venteclef notes. “We realised, particularly with adipose tissue, that the immune cells have to be equipped to deal with the fat, otherwise they will ‘overreact’ and affect adipose tissue function.”
Keywords
EpiFAT, diabetes, epigenome, inflammation, metabolism, adipose tissue, obesity, glucose, immune cells
