Nature: Obesity not only directly affects health, but also delays the body's response to treatment

In modern society, many people's daily routines are changing drastically.
Poor diet and living habits such as staying up late, drinking, overeating and sedentary have become the norm for many people, which has led to the problem of obesity becoming more and more prominent
.

According to the " Report on the Status of Nutrition and Chronic Diseases of Chinese Residents (2020) ", overweight and obesity have become one of the most prominent nutritional problems in China, with an overweight rate of 34.
3% and an obesity rate of 16.
4% among adult residents
.

That is to say, more than half of Chinese adults are overweight or obese

Report on the Status of Nutrition and Chronic Diseases of Chinese Residents (2020) Overweight and obesity have become one of the most prominent nutritional problems in China, with an overweight rate of 34.

On March 30, 2022, researchers from the University of California, San Francisco, the Salk Institute and other institutions published a research paper titled: Obesity alters pathology and treatment response in inflammatory disease in Nature .

Nature Nature Obesity alters pathology and treatment response in inflammatory disease

This study sheds light on the impact of obesity on immune disorders such as allergy and asthma, and suggests a precision treatment approach to obesity-induced immune dysregulation
.

Scientists have long found that obesity affects the treatment of immune diseases
.

For example, when mice with atopic dermatitis, a common allergic skin inflammation, were treated with immunodrugs, their thickened, itchy skin usually healed quickly

"We live in an era of soaring obesity rates, and changes in diet and body composition can affect the immune system, so we must take into account how diseases involving the immune system vary between individuals," said the study's corresponding author, Dr.

Alexander Marson

Different types of T cell responses

Different types of T cell responses

From a molecular biology perspective, obesity is actually a chronic inflammatory state that alters the immune system in a number of ways
.

Clinical reports show that obese patients often have a different course of disease, ranging from infections to allergies to cancer, and respond differently to treatment

The study's first author, Dr.
Sagar Bapat, wanted to explore at the molecular level how obesity affects atopic dermatitis
.

He found that when experimental mice were first fed a high-fat diet to make them obese, and then induced skin inflammation in the mice, the symptoms were more pronounced in the obese mice

Difference analysis between obese mice and normal mice

Difference analysis between obese mice and normal mice Difference analysis between obese mice and normal mice

To understand why, the research team analyzed active immune cells and immune molecules in obese and normal mice, and found that the difference was closely related to helper T cells
.

Human helper T cells can be divided into three categories: TH1, TH2 and TH17
.

Helper T cells help prevent infection, but can also become overactive in autoimmune diseases or allergies

scRNA-seq of helper T cells

scRNA-seq of helper T cells scRNA-seq of helper T cells

In lean mice with atopic dermatitis, the team found that TH2 cells were indeed active, but in obese mice under the same conditions, TH17 cells were instead activated
.

This means that at the molecular level atopic dermatitis is completely different in obese and normal mice,

This raises the question: Do drugs that work in normal individuals also work in obese individuals?

Do drugs that work in normal individuals also work in obese individuals?

Obesity alters drug efficacy

Obesity alters drug efficacy

In recent years, scientists have developed drugs to treat atopic dermatitis by inhibiting the response of TH2 cells
.

However, the study found that when treating obese mice with the drug, instead of relieving their atopic dermatitis, it significantly worsened the disease

It's ironic, Sagar Bapat says, that therapy becomes a powerful counter-therapy
.
You can imagine a scenario where identical twins have atopic dermatitis, but one is obese and the other is a normal weight, and the result is that the same drug works quite differently for two people who are genetically identical
.

The same drug has very different effects on obese and normal mice

The same drug treats obese and normal mice differently

The researchers suspect that dysfunction of the PPAR-gamma protein may mediate the link between obesity and inflammation
.
In 1995, the study's co-corresponding author, Ronald Evans, and his team discovered that PPAR-gamma is a master regulator of fat cells and the target of a drug approved for the treatment of diabetes
.

PPAR-gamma-activating drug improves symptoms in obese mice with atopic dermatitis

PPAR-gamma activating drug improves symptoms in obese mice with atopic dermatitis PPAR-gamma activating drug improves symptoms in obese mice with atopic dermatitis

When the research team treated obese mice with atopic dermatitis with the PPAR-gamma-activating drug rosiglitazone, the mice's skin improved and the disease shifted from TH17 inflammation to TH2 inflammation
.
In addition, drugs targeting TH2 inflammation were able to improve atopic dermatitis in obese animals, just as they did in normal mice
.

back to patient

back to patient

Not only that, but the research team also analyzed data from human allergic disease patients, including 59 atopic dermatitis patients and hundreds of asthma patients who participated in a large longitudinal study
.
They found that obese patients were more likely to have signs of TH17 inflammation, or a reduction in the expected signs of TH2 inflammation
.

While more research in humans is needed, data suggest that, in humans and mice, obesity induces a shift in inflammation that leads to pathological changes in allergic disease and the effectiveness of immunotherapies targeting TH2-related inflammation
.

Overall, this study shows that obesity alters a patient's immune system, which can affect the efficacy of immunotherapy
.
At the same time, the study also pointed out that combining treatments targeting TH2 inflammation with PPAR-γ-activating drugs such as rosiglitazone could treat obese patients with atopic dermatitis
.
These findings guide a very safe, direct-to-human, combination therapy that is already FDA-approved and may have unique therapeutic benefits for certain obese patients!

Original source:

Original source:

Bapat, SP, Whitty, C.
, Mowery, CT et al.
Obesity alters pathology and treatment response in inflammatory disease .
Nature (2022).
https://doi.
org/10.
1038/s41586-022-04536-0.

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