Obesity may alter inflammation on a molecular level, throwing current treatments into question

In a quest to understand why some obese people don’t react to treatment for inflammation, a team of California scientists says it may have uncovered the first glimmer of an answer. 

In a new study published last week in Nature, researchers from the Gladstone Institutes, UCSF and the Salk Institute for Biological Studies reported that among obese mice, there were molecular changes in the immune response to atopic dermatitis that likely impacted their response to treatment. 

To examine the impact of obesity on immune response, the team used mice fed a high-fat diet and compared them to lean mice. After being infected, the obese mice had significantly more inflammation than the control group and worse disease severity even after weight loss. The scientists more closely examined the T-cell response among the two cohorts and found that among obese mice, there was an “unexpected and prominent” response among T helper 17 (TH17) cells. What’s notable is that atopic dermatitis is driven by the onslaught of T helper 2 cells (TH2), thrusting into question obesity’s impact on the immune response on a molecular level. 

Additional data from a cohort of 59 human patients with atopic dermatitis in addition to a longitudinal study of patients with asthma corroborated the top-line findings, namely that obese patients were more likely to have indications of TH17 inflammation.  

To further investigate the impact of this change, the researchers treated the mice with monoclonal antibodies that block the IL-4 and IL-13 cytokines released by Th2. Lean mice elicited a strong immune response whereas for obese mice, not only did they not respond, the disease got worse. 

“The treatment became a robust anti-treatment,” said Dr. Sagar Bapat, M.D., Ph.D., one of the lead authors of the study in a release. “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 implications of these results are wide-ranging for biotechs and pharmas, particularly Sanofi and Regeneron with their FDA-approved drug Dupixent for atopic dermatitis. Dupixent first received FDA approval in 2017 for adults with moderate-to-severe AD but has since expanded its use, most recently to kids six to 11. It’s become nothing short of a cash cow for the French pharma, particularly in 2021 when sales grew more than 50% from the year before, topping €5 billion. Its stunning revenue has attracted competition, specifically from Eli Lilly, which has invested more than $1 billion in lebrikizumab. The potential rival posted phase 3 data last month that analysts called “compelling”. 

The results of the mouse study beg the question: How do you then treat obese patients with severe allergies or inflammation? The positive news is that researchers found that adding an anti-diabetes drug to the treatment regimen was able to stymie TH17 development and improve the response to anti-TH2 treatments. In other words, potentially useful combination therapies could be deployed quickly. 

Nonetheless, the researchers say these results are just scratching the surface and have led to a fresh round of questions regarding the science behind this biological tweak. 

“What we’d like to know more about now is exactly how the T cell switch happens,” said Ye Zheng, Ph.D., another lead author of the study and an associate professor at Salk. “There are more details here to uncover that could have relevance for a host of diseases related to allergy and asthma.”