Nature: obesity not only aggravates the inflammatory pathology, but also resists the treatment response

As we all know, obesity is an important risk factor for cardiovascular disease, type 2 diabetes, hypertension, cancer, chronic kidney disease, a series of skeletal muscle diseases and mental diseases, mainly because obesity is a systemic chronic inflammatory state.

Studies have shown that obesity and metabolic diseases can also affect the immune system, allowing patients to experience different disease severity and treatment response, but the mechanism and impact of this result are still unknown to a large extent.

Recently, in a study published in nature, the research team led by the University of California, San Francisco (UCSF) and the Salk Institute of biology revealed how differences in individual metabolic states have a significant impact on inflammation and treatment responses, and pointed out a new precise immunotherapy strategy to overcome the pathological changes caused by high-fat diet and obesity.

Previous clinical data showed that the same problem also occurred in human patients. From infection, allergy to cancer, obese patients usually experience more serious disease processes and do not respond to some treatments. The team believes that obesity may change the molecular basis of inflammation in mice and humans.

To this end, researchers analyzed the active immune cells and molecules in lean and obese mice with matched genetic backgrounds. They thought they would see high levels of the same pro-inflammatory molecule in obese mice. However, what they observed was a completely different inflammatory response.

As we all know, helper T cells are a kind of T cells, which act as an intermediate process (bridge) in the immune response. Helper T cells can be divided into three types: Th1, Th2 and Th17 cells. These cells help prevent infection, but they can also be hyperactive in autoimmune diseases or allergies. Eczema is considered to be a disease caused by hyperactivity of Th2 cells.

In lean mice with eczema, researchers also observed that Th2 cells were hyperactive. However, in obese mice under the same conditions, Th17 cells were activated. This means that at the molecular level, the response of eczema in obese mice is completely different. This also raises the question: are drugs that are effective for normal or thinner animals also effective for obese animals?

In recent years, scientists have developed drugs to treat eczema by inhibiting the response of Th2 cells. When researchers tried to treat obese mice with one of the drugs, they found that the drugs did not alleviate the skin inflammation of animals, but significantly worsened the disease. Treatment drugs have become "sinners".

In 1995, the team of Ronald Evans, the corresponding author of the study and director of Salk gene expression laboratory, published a study in which PPAR was found- γ It is the main regulator of adipocytes, and it is also an approved drug target for the treatment of diabetes.

Researchers suspect that PPAR- γ The dysfunction of may mediate the link between obesity and inflammation.

When they used a PPAR called rosiglitazone- γ When small molecule agonists were used to treat eczema in obese mice, the skin of animals was improved, and the molecular characteristics of the disease changed from Th17 inflammation to Th2 inflammation. Then, as observed in lean mice, drugs targeting Th2 inflammation can also effectively improve eczema in obese animals.

Researchers said that in essence, this is to immunize obese mice to "degrease" without changing their weight.

Subsequently, the team also analyzed the data of patients with human allergic diseases in a large longitudinal study, including 59 patients with eczema and hundreds of patients with asthma, another disease involving immune system response.

They found that obese patients were more likely to show signs of Th17 inflammation, or the expected signs of Th2 inflammation decreased.

The team said that although more research is needed on humans, these data have suggested that obesity can lead to the transformation of inflammation in humans and mice, which has a significant impact on the pathology of allergic diseases and the effectiveness of immunotherapy targeting Th2 related inflammation.

Dr. Zheng ye, co-author of the study and associate professor of the Nomis Center for immunobiology and microbial pathogenesis of the Salk Institute of biology, said: "we now want to further understand how T cell conversion occurs, and there are more details related to a series of diseases such as allergy and asthma to be found."

In conclusion, this study proves that obesity will lead to more serious disease pathology related to immune "failure", and will transform effective targeted immunotherapy into antitherapy. The study also showed that PPAR γ Agonists help to strengthen the "targeted" immune response and restore the efficacy of immunotherapy in obesity.

Evans said, "our preclinical findings suggest that these FDA approved drugs may have unique combined therapeutic effects on some patients."