A subphenotype of obesity with reduced enteroendocrine GLP-1 synthesis and enhanced tirzepatide response
Abstract
Background & Aims: Obesity is a heterogeneous disease characterized by different pathophysiological and behavioral traits that influence response to GLP-1-based therapies. We previously identified an obesity phenotype characterized by fast gastric emptying and increased postprandial hunger. We aimed to elucidate pathophysiologic mechanisms in this phenotype by evaluating plasma enteroendocrine hormones and mucosal gene expression, and to evaluate treatment response to tirzepatide across subphenotypes.
Methods: 483 adults with obesity underwent solid meal gastric emptying (SGE) by scintigraphy, postprandial appetite assessment using visual analog scale (VAS), and plasma enteroendocrine hormone profiling. Gaussian mixed modeling identified phenotypic clusters. Associations with plasma short-chain fatty acids (SCFAs) and fecal metagenomics were explored. A separate cohort (n=31) underwent colonic mucosal biopsies with quantification of GCG (GLP-1) and PYY mRNA. Retrospective evaluation of weight loss in participants treated with tirzepatide among each cluster was performed (n=61).
Results: Three clusters were identified based on SGE and GLP-1. One cluster demonstrated fast SGE, increased postprandial hunger, and discordantly low postprandial GLP-1 (termed dc-GE/GLP-1; n=130, 26.9%), as well as lower plasma PYY and CCK. dc-GE/GLP-1 showed higher plasma SCFA levels, without significant differences in fecal microbial composition. Compared with concordant clusters (c-GE/GLP-1; n=353, 73.1%), dc-GE/GLP-1 had decreased mucosal mRNA expression of GCG (GLP-1) and PYY. At 6-months of tirzepatide, dc-GE/GLP-1 was associated with greater weight loss compared with c-GE/GLP-1 (21.5% vs 11.7%).
Conclusions: We identified a subphenotype of obesity with fast gastric emptying and discordantly low GLP-1 plasma levels, reduced mucosal hormone synthesis, and enhanced weight loss to tirzepatide. Further studies are needed to identify mechanisms contributing to GLP-1 deficiency in this subphenotype of obesity.
Authors: Alexander L Ticho, Alison N McRae, Lizeth Cifuentes, Thomas Fredrick, Diego Anazco, Maria A Espinosa, Juan M Garcia Cordova, Michael Romanos, Jose Villamarin, Stephen Johnson, Ryan Lennon, Maria D Hurtado Andrade, Jun Chen, Michael Camilleri, Andres J Acosta
Journal: Gastroenterology