When mice with atopic dermatitis are treated with drugs that target the immune system, their itchy skin generally heals quickly. However, scientists have now discovered that the same treatment in obese mice makes their skin worse instead. A new study sheds light on how obesity can change the immune system and how clinicians might be able to better treat allergies and asthma in obese people.
The new study is published in the journal Nature in a paper titled, “Obesity alters pathology and treatment response in inflammatory disease,” and led by researchers at Gladstone Institutes, the Salk Institute for Biological Studies, and the University of California, San Francisco (UCSF).
“Decades of work have elucidated cytokine signaling and transcriptional pathways that control T-cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic, and inflammatory diseases,” the researchers wrote. “Recent evidence indicates that obesity and metabolic disease can also influence the immune system although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses.”
“We’re living in an era when the rate of obesity is increasing around the world,” said Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology and a senior author of the study. “Changes in diet and body composition can affect the immune system, so we have to think about how diseases that involve the immune system might differ between individuals.”
“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,” said Ronald Evans, PhD, senior author of the study, and director of Salk’s Gene Expression Laboratory and the March of Dimes chair in molecular and developmental biology at Salk.
During his graduate studies at Salk and subsequent research in the Marson lab, Sagar Bapat, MD, PhD—now a pathologist and faculty at UCSF—wanted to know, at a molecular level, how obesity affected atopic dermatitis. He discovered that when mice were made obese by eating a high-fat diet prior to the induction of dermatitis, they developed more severe disease than lean animals.
“What we were expecting to see in the obese mice was just a greater degree of the same kind of inflammation,” said Bapat. “Instead, we saw a completely different kind of inflammation.”
Scientists had considered atopic dermatitis a TH2 disease; that means the TH2 cells are the ones causing the skin inflammation.
In mice with atopic dermatitis, the researchers observed that the TH2 cells were active. In obese mice with the same condition, however, TH17 cells were activated, which meant at a molecular level, atopic dermatitis was completely different in the obese mice.
When Bapat and his colleagues treated obese mice with a drug known to lessen atopic dermatitis, it made the disease significantly worse.
“The treatment became a robust anti-treatment,” said Bapat. “This suggests that you can have identical twins show up to the hospital with the same disease, but if one is obese and one is lean, maybe the same drug won’t work on both.”
The researchers suspected that dysfunction in a protein called PPAR-gamma might be mediating the link between obesity and inflammation. In 1995, Evans and his team discovered that PPAR-gamma was a master regulator of fat cells and a target of an approved drug for diabetes.
When the scientists treated obese mice with atopic dermatitis with one of these PPAR-gamma activating drugs, called rosiglitazone, the animals’ skin improved and the molecular profile of their disease switched back from TH17 to TH2 inflammation. Moreover, the drugs aimed at the TH2 inflammation were then, almost as in lean mice, able to improve the obese animals’ atopic dermatitis.
“Essentially, we immunologically ‘de-fattened’ obese mice without changing their body weight,” said Bapat.
More studies are needed but the study demonstrates how obesity causes a switch in inflammation that has consequences for the pathology of allergic disease and the effectiveness of immune therapies that target TH2-associated inflammation.
“What we’d like to know more about now is exactly how the T-cell switch happens,” said senior author Ye Zheng, PhD, an associate professor in the NOMIS Center for Immunobiology and Microbial Pathogenesis at Salk. “There are more details here to uncover that could have relevance for a host of diseases related to allergy and asthma.”
“This is a case where our scientific discovery could have a very safe and quick application to therapy in people,” said Evans. “Our preclinical findings suggest that these already FDA approved drugs may have a unique co-treatment benefit in certain patients.”