Highlight
A multicohort study in adults with obesity identified a distinct subgroup characterized by fast solid-meal gastric emptying, greater postprandial hunger, and unexpectedly low postprandial GLP-1 levels.
This phenotype, termed discordant gastric emptying/GLP-1 (dc-GE/GLP-1), also showed lower circulating PYY and CCK and reduced colonic mucosal expression of GCG and PYY, supporting impaired enteroendocrine hormone synthesis rather than simply altered hormone release.
In a retrospective treatment analysis, patients with this subphenotype had substantially greater 6-month weight loss with tirzepatide than participants in concordant clusters, suggesting clinically meaningful predictive enrichment for response.
The findings support a precision-medicine framework in obesity, although prospective validation, mechanistic confirmation, and practical bedside phenotyping tools are still needed.
Background
Obesity is increasingly understood as a heterogeneous chronic disease rather than a single entity defined only by excess adiposity. Patients differ in appetite regulation, gastric motor function, nutrient sensing, reward pathways, energy expenditure, insulin sensitivity, and response to pharmacotherapy. This heterogeneity has major clinical implications, particularly now that highly effective incretin-based anti-obesity therapies are available but remain costly, variably tolerated, and not uniformly effective.
GLP-1, or glucagon-like peptide-1, is an enteroendocrine hormone produced primarily by intestinal L cells after nutrient exposure. It slows gastric emptying, promotes satiety, enhances insulin secretion in a glucose-dependent manner, and contributes to weight regulation. Related gut peptides, including peptide YY (PYY) and cholecystokinin (CCK), also modulate satiation and meal termination. Reduced endogenous satiety signaling could plausibly contribute to obesity in at least some patients.
Prior work by this investigative group had described a phenotype of obesity associated with accelerated gastric emptying and increased postprandial hunger. The present study extends that observation by asking whether this behaviorally and physiologically recognizable pattern reflects an underlying enteroendocrine defect, and whether that defect identifies patients who respond especially well to tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist approved for obesity treatment.
The translational importance is clear: if a subgroup of patients has relative endogenous GLP-1 deficiency, they may be especially responsive to potent incretin replacement or augmentation strategies. Such a concept would move obesity treatment closer to mechanism-based therapy rather than empiric drug selection.
Study Design and Methods
Overall study framework
Ticho and colleagues evaluated 483 adults with obesity who underwent detailed phenotyping that included solid gastric emptying scintigraphy, postprandial appetite assessment, and plasma enteroendocrine hormone measurement. Using Gaussian mixed modeling, the investigators identified phenotypic clusters based on gastric emptying and GLP-1-related patterns.
The study then examined potential mechanistic correlates, including circulating short-chain fatty acids (SCFAs) and fecal metagenomics. In a separate cohort of 31 participants, colonic mucosal biopsies were analyzed for expression of GCG, the precursor gene for GLP-1, and PYY mRNA. Finally, a retrospective treatment analysis assessed 6-month weight loss with tirzepatide in 61 participants distributed across the identified clusters.
Core phenotyping variables
The major phenotyping axes were solid meal gastric emptying and postprandial GLP-1 response. Gastric emptying scintigraphy remains a reference method for quantifying gastric transit and is particularly relevant in obesity because gastric motor patterns can influence meal size, nutrient delivery to the small intestine, satiation, and hormone release. Appetite was assessed after meals using visual analog scales, allowing symptom-level correlation with physiologic measurements.
Plasma enteroendocrine profiling extended beyond GLP-1 to include PYY and CCK, providing a broader view of satiety hormone biology. The use of multiple biologic levels, including plasma markers and tissue mRNA expression, strengthened the mechanistic inference.
Subphenotype definition
The principal abnormal cluster was labeled dc-GE/GLP-1, meaning discordant gastric emptying and GLP-1. These patients had fast gastric emptying but lower-than-expected postprandial GLP-1 levels, a mismatch that suggests impaired enteroendocrine capacity rather than a physiologic increase in GLP-1 secretion in response to more rapid nutrient transit. The comparator group comprised concordant gastric emptying/GLP-1 clusters, collectively termed c-GE/GLP-1.
Key Findings
Three clusters emerged, with one biologically distinct subgroup
Among 483 adults with obesity, the modeling approach identified three clusters. The biologically most notable cluster was dc-GE/GLP-1, comprising 130 participants, or 26.9% of the cohort. The remaining 353 participants, or 73.1%, fell into the concordant clusters.
The key feature of dc-GE/GLP-1 was the combination of fast solid gastric emptying and reduced postprandial GLP-1. Clinically, this subgroup also reported increased postprandial hunger, linking the hormonal signature to a meaningful eating-related phenotype rather than an isolated laboratory abnormality.
Broader satiety hormone deficiency was present
The endocrine signal was not confined to GLP-1. Participants with dc-GE/GLP-1 had lower plasma PYY and CCK levels than the concordant groups. This broader reduction in satiety-associated peptides suggests that the phenotype may reflect generalized enteroendocrine dysfunction, or at least impaired nutrient-triggered hormone synthesis and/or release in a subset of enteroendocrine pathways.
That observation matters mechanistically because satiety regulation is redundant and network-based. A patient with low GLP-1 but intact PYY and CCK signaling might compensate. By contrast, simultaneous attenuation of several gut-derived satiety signals could plausibly produce stronger hunger after meals and greater difficulty sustaining weight loss without targeted therapy.
Mucosal gene expression supported impaired hormone synthesis
In the separate biopsy cohort, dc-GE/GLP-1 was associated with reduced colonic mucosal mRNA expression of GCG and PYY. This is among the most important findings in the paper because it shifts the mechanistic interpretation from altered hormone kinetics alone toward reduced endogenous production capacity. In other words, the low postprandial GLP-1 signal appears to be rooted, at least in part, in reduced transcriptional programming of enteroendocrine hormone precursors.
Although mRNA expression cannot by itself prove reduced peptide secretion at all relevant intestinal sites, the tissue-level data align well with the plasma findings and improve biological plausibility. Together, they support the concept of an obesity subphenotype with reduced endogenous satiety hormone synthesis.
SCFAs were higher, but fecal metagenomics did not clearly explain the phenotype
The dc-GE/GLP-1 group showed higher plasma short-chain fatty acid levels. This is intriguing because SCFAs, including acetate, propionate, and butyrate, have often been linked to enteroendocrine signaling, gut barrier function, and host metabolic regulation. One might have predicted lower SCFAs in a group with impaired GLP-1 biology; instead, the opposite was observed.
At the same time, fecal microbial composition did not differ significantly between groups. This negative result is important. It suggests that standard fecal taxonomic profiling may not capture the biologic features responsible for altered enteroendocrine output, or that differences reside in microbial function, luminal metabolite handling, host absorption, or mucosal microbe-host interactions rather than broad compositional changes. It also cautions against overly simple gut microbiome explanations for complex endocrine phenotypes.
Tirzepatide response was substantially greater in the low-GLP-1 subgroup
The most clinically striking result came from the retrospective tirzepatide analysis. At 6 months, participants with dc-GE/GLP-1 achieved 21.5% weight loss compared with 11.7% in the concordant groups. This roughly 10 percentage point absolute difference is large and, if confirmed prospectively, would be highly actionable.
The magnitude of separation strongly suggests that endogenous pathophysiology may shape therapeutic responsiveness to incretin-based treatment. A patient subgroup marked by deficient native satiety signaling may derive amplified benefit from pharmacologic receptor agonism. This observation is conceptually analogous to replacement therapy, although tirzepatide is not a simple hormone replacement agent and also engages GIP signaling.
The abstract does not report confidence intervals, adjusted effect estimates, or formal interaction statistics for this treatment analysis, so the exact robustness of the difference cannot be fully assessed from the available information. Even so, the signal is large enough to merit serious clinical and research attention.
Clinical Interpretation
Why this phenotype may matter in practice
Current obesity treatment often proceeds by trial and error. Clinicians choose among lifestyle therapy, bariatric procedures, and medications such as semaglutide, tirzepatide, phentermine/topiramate, naltrexone/bupropion, or orlistat, usually without a validated biologic framework for matching patient to treatment. This study offers a possible example of precision obesity medicine: identify a subgroup with low endogenous enteroendocrine satiety signaling and preferentially treat with a potent incretin-based agent.
The phenotype also makes physiologic sense. Fast gastric emptying may reduce gastric distension-mediated satiation and accelerate nutrient transit. If that is paired with unexpectedly low GLP-1, PYY, and CCK signaling, the normal “meal termination” response may be blunted. Patients may then experience earlier return of hunger after meals and find caloric restriction particularly difficult. Tirzepatide, by enhancing GLP-1 receptor signaling and adding GIP receptor activity, may directly target this deficit.
Potential bedside implications
For now, the phenotype is not immediately ready for routine practice because the study used detailed scintigraphy, hormone profiling, and in a subset, tissue biopsies. These tests are not standard obesity clinic tools. However, the work points toward more practical future strategies, such as simplified gastric emptying tests, validated symptom clusters, postprandial biomarker panels, or composite prediction models that identify likely “enteroendocrine-deficient” obesity.
If prospectively validated, such a model could help clinicians prioritize incretin-based treatment in patients most likely to respond, justify payer coverage with mechanism-based arguments, and spare some patients ineffective sequencing of alternative therapies.
Mechanistic Considerations
The central mechanistic insight is that not all obesity is characterized by exaggerated appetite due only to behavior or environment; in some patients, there may be a measurable deficit in endogenous satiety hormone synthesis. Reduced GCG and PYY transcription in colonic mucosa suggests either lower density of relevant enteroendocrine cells, altered cell differentiation, impaired transcriptional regulation, or chronic adaptive changes in response to diet, inflammation, neural signaling, or metabolic state.
The elevated plasma SCFAs complicate the story. Since SCFAs can stimulate L-cell activity under some conditions, the finding raises several possibilities: host responsiveness to SCFAs may be impaired; circulating levels may not reflect mucosal exposure; altered absorption kinetics may be present; or elevated SCFAs could represent a compensatory, not causative, phenomenon. Functional microbiome studies, intestinal spatial transcriptomics, and enteroendocrine cell phenotyping will likely be needed to resolve these questions.
Another unresolved point is the role of GIP signaling in tirzepatide response. Greater efficacy in the dc-GE/GLP-1 group could indicate benefit from GLP-1 replacement in a low-GLP-1 state, but it does not exclude an important contribution from GIP receptor agonism. Comparative studies with semaglutide or other selective GLP-1 receptor agonists would help determine whether the response enrichment is tirzepatide-specific or generalizable across incretin-class medications.
Strengths and Limitations
Strengths
This work has several notable strengths. First, it uses multimodal phenotyping that links physiology, symptoms, circulating biomarkers, tissue-level gene expression, and treatment response. Second, the identified subgroup is clinically coherent: fast gastric emptying, more hunger, lower satiety hormones, and greater benefit from a targeted therapy. Third, the prevalence of the phenotype, about one-quarter of the cohort, suggests it is not a rare curiosity but potentially a meaningful clinical subgroup.
Limitations
Several limitations should temper interpretation. The tirzepatide analysis was retrospective and involved only 61 treated participants, making confounding and selection bias important concerns. The abstract does not specify how tirzepatide dosing, adherence, background lifestyle intervention, or coexisting diabetes status were handled, all of which could influence weight loss magnitude.
The biopsy cohort was small, with only 31 participants, so tissue-expression findings, while compelling, require replication. The cluster-derived phenotype depends on specialized testing and statistical modeling that may not transfer directly to broader practice settings. The study population characteristics, including race, ethnicity, sex distribution, diabetes prevalence, and degree of obesity, are not detailed in the abstract, limiting assessment of generalizability.
In addition, the fecal metagenomics result was largely negative, but absence of compositional differences does not exclude meaningful functional microbial variation. Finally, causality cannot be established: reduced GLP-1 synthesis may contribute to obesity, result from obesity, or reflect a parallel process.
Relation to Existing Literature
The findings fit with an expanding literature showing that gastric emptying and gut hormone dynamics influence eating behavior and obesity phenotypes. Work from Camilleri, Acosta, and colleagues has previously emphasized heterogeneity in gastric motor function and satiation among people with obesity. Separately, incretin therapies such as semaglutide and tirzepatide have demonstrated substantial efficacy in randomized trials, but marked interindividual variability in weight loss has remained clinically obvious.
Tirzepatide produced approximately 15% to 21% mean weight loss across dose groups in the SURMOUNT-1 trial, confirming the high efficacy of dual incretin agonism in obesity. What has been missing is a reproducible biologic framework for predicting who responds best. The present study begins to fill that gap by suggesting that low endogenous satiety hormone production could be one such framework.
Whether similar predictive phenotypes exist for other obesity mechanisms, such as hedonic eating, reduced satiation from impaired gastric accommodation, insulin hypersecretion, or altered energy expenditure, is an important next question for the field.
Implications for Research and Practice
The immediate practical message is not that all patients with obesity should undergo gastric emptying scintigraphy or mucosal biopsy. Rather, the study should prompt clinicians and investigators to think beyond body mass index and recognize that mechanism-based obesity classification may soon become feasible.
Near-term research priorities include prospective validation of the dc-GE/GLP-1 phenotype, testing whether it predicts response to semaglutide as well as tirzepatide, developing simpler diagnostic surrogates, and clarifying whether the phenotype is stable over time or modifiable with diet, surgery, or microbiome-directed therapy. It will also be important to determine whether this subgroup differs in cardiometabolic risk, glycemic response, gastrointestinal adverse effects, or weight regain after stopping therapy.
For clinicians, the study reinforces the value of careful symptom phenotyping. Patients who describe rapid return of hunger after meals and who appear to have diminished postprandial satiety may represent a biologically meaningful subgroup worthy of preferential consideration for potent incretin therapy, even before formal biomarkers become available.
Conclusion
This study identifies a clinically and biologically plausible subphenotype of obesity characterized by fast gastric emptying, heightened postprandial hunger, low postprandial GLP-1, lower PYY and CCK, and reduced mucosal expression of GCG and PYY. Most importantly, this subgroup experienced markedly greater 6-month weight loss with tirzepatide than concordant comparison clusters.
The work strengthens the case for precision medicine in obesity by linking pathophysiology to treatment response. However, the findings should be viewed as hypothesis-generating until prospectively validated in larger and more diverse populations. If confirmed, this phenotype could become an early example of actionable biologic stratification in obesity care.
Funding and ClinicalTrials.gov
The abstract does not report funding details or a ClinicalTrials.gov registration number. Readers should consult the full Gastroenterology publication for source funding, disclosures, and protocol details.
References
1. Ticho AL, McRae AN, Cifuentes L, Fredrick T, Anazco D, Espinosa MA, Garcia Cordova JM, Romanos M, Villamarin J, Johnson S, Lennon R, Hurtado Andrade MD, Chen J, Camilleri M, Acosta AJ. A subphenotype of obesity with reduced enteroendocrine GLP-1 synthesis and enhanced tirzepatide response. Gastroenterology. 2026-06-05. PMID: 42250890.
2. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.
3. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.
4. Acosta A, Camilleri M. Gastrointestinal contributions to obesity: pathophysiology and therapeutic implications. Gastroenterology. Relevant prior reviews and mechanistic work from this field support the biologic rationale for gastric motor and enteroendocrine phenotyping in obesity.
