Obesity alters the response to anti-inflammatory treatment

Obesity is a growing health problem worldwide. Studies estimate that, by the year 2030, more than half of adults in the U.S. will be obese. Excess weight is associated with an increased risk of many health conditions. It’s also thought to impact the immune system. But the mechanisms in the body that lead to these effects aren’t fully understood.

A team led by researchers from the Gladstone Institutes, the Salk Institute, and the University of California, San Francisco, has been studying these mechanisms and how they relate to inflammatory diseases, which involve problems with the immune system. In their new study, they examined differences in the immune response between obese and lean mice with atopic dermatitis, an itchy skin condition also known as eczema.

The work was funded in part by several NIH components, including the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Results were published on March 30, 2022, in Nature.

The team first tracked the development of eczema in obese and lean mice. They found that obese mice developed more inflammation and more severe eczema. This increased inflammation occurred even after obese mice lost weight. Similar results were seen in an experimental model of asthma, with obese mice developing more inflammation.

The researchers next looked in detail at immune cells called T cells in lean and obese mice with eczema. Lean mice had more TH2 cells, a class of T cells known to play a role in the development of eczema. Obese mice had more of a class of T cells called TH17. These cells trigger a different type of inflammation.

Similar trends were seen in blood samples taken from people. Markers of TH17 cell activity increased along with body mass index (BMI) in a database of serum collected from people with eczema. Conversely, in samples from patients with severe asthma, TH2 cell activity decreased as BMI increased.

Drugs that block TH2 cell activity are used in the treatment of severe eczema as well as asthma and other inflammatory conditions. The researchers tested antibodies to block TH2 cell activity in lean and obese mice with severe eczema. While the antibodies reduced skin inflammation in lean mice as expected, they made the condition worse in obese mice. Analysis of immune cells suggested that blocking TH2 cell activity in the obese mice worsened other forms of inflammation.

Further study found that obese mice appear to have less activity of a protein called PPARɣ in their TH2 cells. When the researchers engineered lean mice to lack PPARɣ, their inflammatory response resembled that of obese mice.

Drugs that increase PPARɣ activity increase insulin sensitivity and are approved for the treatment of type 2 diabetes. The researchers found that giving one of these drugs to obese mice changed their inflammatory response to resemble that of lean mice. It also restored their sensitivity to the antibodies that block TH2 cell activity.

“Our findings demonstrate how differences in our individual metabolic states can have a major impact on inflammation, and how available drugs might be able to improve health outcomes,” says Dr. Ronald Evans from the Salk Institute, who helped lead the work.