Cell MetabWeight LossDecember 2, 2025

Gut enteroendocrine cell activation using a combination of GPR119 and GPR40 agonists results in synergistic hormone secretion in mice and humans.

Sebhat IK, Murphy MJM, Zheng S, Lovelett RJ, Engelstoft M, Kosinski D, Yang X, Dunn V, Whang J, Lombardo MG, Heilbut A, Terracina G, Nicholas N, Leitner M, Consolati MJ, Chan B, Poterewicz G, Vance A, Liu J, Weber AE, Lauring B, Thornberry N, Pinto S

View on PubMed DOI: pii: S1550-4131(25)00485-1. 10.1016/j.cmet.2025.11.001

Key Finding

Scientists developed a drug combination that activates gut hormone-producing cells so effectively that it created higher levels of satiety hormones than bariatric surgery achieves in Phase 1 human trials.

What This Study Found

Think of your gut as having special hormone factories called enteroendocrine cells (EECs) that produce satiety signals like GLP-1 when you eat. Bariatric surgery works partly because it supercharges these factories, flooding your body with 'I'm full' messages. These researchers essentially reverse-engineered this process by mapping out these gut factories in unprecedented detail and discovering that some cells have two specific 'on switches' - receptors called GPR40 and GPR119. They then created two targeted drugs (K-757 and K-833) that flip both switches simultaneously. It's like having two keys that, when used together, unlock a vault of satiety hormones. When tested in both mouse gut tissue and human gut tissue grown in lab dishes, the combination created a synergistic effect - meaning 1+1 equaled more than 2. In mice, this translated to better blood sugar control and weight loss. Most remarkably, when tested in Phase 1 human trials, the circulating gut hormone levels exceeded what's typically seen after bariatric surgery - essentially achieving the hormonal benefits of surgery through pills.

Statistics Decoded

The abstract doesn't provide specific numerical data, but mentions 'synergistic hormone secretion' which means the two drugs together produced more hormone release than each drug alone added up to. The phrase 'exceeded levels observed in bariatric surgery' in Phase 1 trials suggests the hormone response was stronger than the gold standard surgical intervention, though exact fold-increases aren't specified. 'Efficacious in improving glucose tolerance and promoting weight loss in mice' indicates statistically meaningful improvements in both blood sugar handling and body weight, but specific percentages aren't provided in this abstract.

Why This Matters

This could potentially offer the metabolic benefits of bariatric surgery - currently the most effective obesity treatment - in pill form, making it accessible to millions more patients who can't or won't undergo surgery. The fact that hormone levels exceeded those seen with surgery suggests this approach might be even more powerful than our current gold standard.

Original Abstract

A leading hypothesis for the effectiveness of bariatric surgery for weight loss is supraphysiologic activation of gut enteroendocrine cells (EECs), which results in elevated postprandial levels of satiety hormones, including glucagon-like peptide-1 (GLP-1). Here, we describe direct targeting of EECs to mimic effects of bariatric surgery. Advanced technologies were used to obtain a comprehensive understanding of EEC diversity, resulting in the identification of cells that express both satiety hormones and target receptors, including GPR40 (FFAR1) and GPR119. We developed gut-targeted agonists of these receptors, K-757 and K-833, and demonstrated synergistic hormone secretion in murine and human enteroids. The combination was efficacious in improving glucose tolerance and promoting weight loss in mice. The levels of circulating gut hormones observed in phase 1 trials exceeded levels observed in bariatric surgery, warranting further clinical investigation of these compounds for weight loss and glucose control.