The role of adipose tissue on systemic inflammation and metabolic dysregulation in obese asthma

Nearly half of adults will be obese by 2030. Increased obesity rates also presage higher rates of obesityassociated complications, including 250,000 projected new cases of obesity-associated asthma annually. Obesity-associated asthma is poorly understood, has decreased response to inhaled corticosteroids, and often fails to improve with newer cytokine-targeted biologic therapies. Several lines of evidence show that adipose tissue is a critical regulator of metabolic dysregulation and systemic inflammation, and likely contributes to respiratory disease. However, our understanding of how obese AT inflammation influences respiratory disease, and vise-versa, is entirely unknown. Dr. Koethe (co-I) recently used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to create a single-cell, multiomic adipose tissue atlas of individuals with obesity.

Preliminary data for this application showed that a distinct inflammatory cell signature is enriched in the adipose tissue of individuals with obesity. Adipose tissue cells mediate metabolic dysregulation in obesity through the production of pro-inflammatory adipokines and cytokines. Based on these data, we hypothesize that chronic adipose tissue inflammation is heightened during asthma with comorbid obesity and synergistically drives systemic inflammation and metabolic dysregulation in obesity-associated asthma. To test our hypothesis, we will leverage unbiased CITE-seq to define changes in adipose tissue cellular composition and transcriptional programs using adipose tissue biopsies from our two NIH and AHA-supported clinical trials of patients with obesity and with or without asthma in the following aims:

Aim 1: Test the hypothesis that asthma enhances chronic adipose tissue inflammation in patients with obesity.

Aim 2: Test the hypothesis that adipose tissue inflammation drives systemic inflammation and metabolic dysregulation in obesity-associated asthma.