A Subphenotype of Obesity With Reduced Enteroendocrine Glucagon-Like Peptide 1 Synthesis and Enhanced Tirzepatide Response.

BACKGROUND & AIMS: Obesity is a heterogeneous disease characterized by different pathophysiological and behavioral traits that influence response to glucagon-like peptide 1 (GLP-1)-based therapies. We previously identified an obesity phenotype characterized by fast gastric emptying (GE) and increased postprandial hunger. We aimed to elucidate pathophysiological mechanisms in this phenotype by evaluating plasma enteroendocrine hormones and mucosal gene expression and to evaluate treatment response to tirzepatide across subphenotypes. METHODS: A total of 483 adults with obesity underwent solid meal GE (SGE) by scintigraphy, postprandial appetite assessment using a visual analogue scale, and plasma enteroendocrine hormone profiling. Gaussian mixed modeling identified phenotypic clusters. Associations with plasma short-chain fatty acids and fecal metagenomics were explored. A separate cohort (n = 31) underwent colonic mucosal biopsies with quantification of GCG (GLP-1) and PYY messenger RNA. 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 peptide YY and cholecystokinin. dc-GE/GLP-1 showed higher plasma short-chain fatty acid 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 messenger RNA 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 GE 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.