An immune process that regulates inflammation in adipose tissue could offer new therapeutic approaches for obesity. A recent study reveals how obese immune cells are linked to weight gain.
That immune cells have far more duties than inflammation to cause and fight infections has been known for a long time. Inflammatory cells play an important role in regulating numerous metabolic processes. Irish and German scientists have now discovered that immune cells in the adipose tissue among other things to one weight gain being able to lead. A dysregulation of the balance between pro- and anti-inflammatory cells the progression of a obesity favored. The central focus that Science Translational Medicine published work is the immunoregulatory molecule PD-1.
Adipose immune cells
In their study, research groups from the School of Medicine at Trinity College Dublin and the University Hospital Erlangen have the function of the immune checkpoint PD-1 (Programmed cell Death protein 1) examined more closely. In the case of a regular immune response, PD-1 inactivates after binding to its ligand PD-L1, T cells and thus prevents an excessive immune response from cytotoxic cells.
For the first time, the researchers have now published a comprehensive study on the effects of small changes in this immune process in adipose tissue.
First, they proved that PD-L1 expression has a direct impact on the development of obesity. To this end, they compared the course of obesity in wild-type and PD-L1knockout mice. Both groups received a high-fat diet, an established technique to induce obesity in mouse models. Those isolated from the adipose tissue of the now obese mice macrophagesCD4+ T cells and in particular dendritic cells showed a significantly increased expression of PD-L1. It was also found that PD-L1 knockout mice were significantly more obese after the same period of time despite a comparable initial weight (23.69 ± 1.00 g and 23.86 ± 0.88 g) and additionally one insulin resistance developed.
In addition, the number of immune cells such as ILC2s, Eosinophils and macrophages in the knockout mice were greatly reduced. The scientists were thus able to show that changes in the PD-1 pathway in mice were associated with a dramatic development of obesity and diabetes, as well as immunological impairments.
Antibodies against obesity?
To find out whether therapeutic intervention in the PD-1 pathway might affect adipose tissue homeostasis and metabolic health in a similar way, the researchers used Immune Checkpoint Inhibitors. Obese wild-type mice were treated with PD-1-blocking monoclonal antibodies or placebo treated. The mice that received a blocking antibody every three days (six doses total) showed no signs of systemic inflammation or side effects. However, anti-PD-L1 antibody treatment resulted in a significant (P<0.05) decrease in glucose tolerance compared to the untreated control.
The researchers concluded that blocking PD-1 led to a deterioration in metabolism. They also observed increasing weight gain in the antibody-treated mice, similar to their results in PD-L1 knockout animals. In future experiments, the researchers hope to be able to manipulate certain cell populations by regulating the PD-1 checkpoint in order to counteract obesity.
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From mouse to human
After the fascinating discoveries in the mouse model, the researchers were interested in whether PD-1 is also relevant to obesity in humans. Obesity is a global health risk Diabetes, cardiovascular diseases and Krebs to get sick. New therapies are needed to combat this problem.
Therefore, the scientists analyzed the PD-L1 expression in the adipose tissue of people with a slim build (BMI 20 to 25 kg/m2) and obese people (BMI > 30 kg/m2 ). They found a significant (P 40kg/m2). This upregulation of PD-L1 in human adipose tissue was positively correlated with BMI. However, an influence on glucose tolerance in the context of diabetes, similar to the results in the mouse model, could not be shown. However, the scientists observed a significantly (P < 0.001) higher mRNA-Expression of the proinflammatory cytokine TNF in the obese cohort, underscoring the immunological impairment in obesity already suspected in the mouse model.
This newly explored influence of immunological processes in adipose tissue advances the understanding of how the immune system correlates with weight gain and can lead to diseases such as obesity and type 2 diabetes. It will be interesting to explore how these processes can be manipulated to help people with metabolic syndrome.
Image source: Scott Webb, Unsplash