Obesity subphenotype with reduced enteroendocrine GLP-1 synthesis shows enhanced tirzepatide response

Obesity is a complex, heterogeneous disease, leading to varied responses to current therapies like GLP-1-based agonists. Understanding these differences is crucial for personalized medicine. This study aimed to identify distinct pathophysiological subphenotypes of obesity by evaluating enteroendocrine hormone profiles and gene expression, particularly focusing on GLP-1 and PYY synthesis. Previous research identified an obesity phenotype with fast gastric emptying and increased postprandial hunger, suggesting a potential underlying hormonal imbalance that could influence treatment efficacy.

Researchers studied 483 adults with obesity, assessing solid meal gastric emptying (SGE) via scintigraphy, postprandial appetite using a visual analog scale (VAS), and plasma enteroendocrine hormone levels. Gaussian mixed modeling identified distinct phenotypic clusters. Associations with plasma short-chain fatty acids (SCFAs) and fecal metagenomics were explored. A separate cohort of n=31 underwent colonic mucosal biopsies to quantify GCG (GLP-1) and PYY mRNA expression. Finally, a retrospective analysis evaluated weight loss in n=61 participants treated with tirzepatide across the identified clusters.

Three distinct obesity clusters were identified based on SGE and GLP-1 responses. One specific cluster, termed dc-GE/GLP-1 (n=130, representing 26.9% of the cohort), exhibited fast SGE, increased postprandial hunger, and discordantly low postprandial GLP-1 levels. This dc-GE/GLP-1 group also showed lower plasma PYY and CCK levels, alongside higher plasma SCFA levels, though without significant differences in fecal microbial composition. Compared to concordant clusters (c-GE/GLP-1; n=353, 73.1%), the dc-GE/GLP-1 subphenotype had significantly decreased mucosal mRNA expression of GCG (GLP-1) and PYY.