Epigenomic Changes in Macrophages Drive Type 2 Diabetes in Obesity

Epigenomic Changes in Macrophages Drive Type 2 Diabetes in Obesity

While obesity is a risk factor for type 2 diabetes, not all obese people have a disturbed glucose metabolism.

New research from Karolinska Institutet in Sweden and the Institute of Health and Medical Research (INSERM) in France reported that epigenomic changes, triggered by a GPS2 containing co-repressor complex which controls the epigenome in macrophages, are linked to diabetes development following in obesity’s track.

All genes are present in all cells of the body, but the activity of a gene, determining whether it is a silent component of a cell or an active player contributing to cellular functions is, controlled by epigenomic changes. Alterations come in chemical groups added to, or removed from, the DNA molecule, and can be triggered by environmental factors that fluctuating over a lifetime.

The research group studied co-repressor complex, a factor that works by inducing epigenetic changes. They discovered the complex, containing the molecule GPS2, controls the epigenome in macrophage cells. The cells are known contributors to inflammatory processes triggered by metabolic conditions such as obesity.

The study, Loss of the corepressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes, published inNature Medicine , combined research using mouse models with studies of human tissue.

The team found that obese people with diabetes have lower levels of GPS2 in fat tissue, in comparison to non-diabetics. The finding led the researchers to engineer a mouse lacking GPS2 in macrophages, in order to investigate the consequences of the lower levels.

These mice were fed a high-fat diet, which rendered normal mice obese. But the GPS2 mice did not become obese. Instead, researchers observed inflammation in the fat tissue and high resistance to insulin and fatty liver; both features that the genetically altered mice developed faster than obese counterparts.

The situation can be compared to “metabolically healthy” and “unhealthy obese” people, according to a press release.

“The findings point to a causal, and potentially reversible, relationship between inappropriate expression and function of the complex, the extent of adipose tissue inflammation, and systemic insulin resistance towards type 2 diabetes” said Nicolas Venteclef, of the Cordeliers Research Centre, INSERM, in Paris.

Scientists believed that the epigenomic changes worsened inflammation in the situation of metabolic stress tied to obesity and diabetes, which started a downward spiral of disease changes.

“The study highlights the value of combining mouse and human studies in identifying molecular mechanisms underlying disease”, said Eckardt Treuter, who led the Karolinska Institutet research team. “In particular, the mouse experiments provide strong evidence that epigenome alterations that originate in either macrophages or fat cells can be the cause, and not just a consequence, of obesity complications towards diabetes.”

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