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

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

  • Cell Metab. 2026 Jan 6;38(1):50-64.e12. doi: 10.1016/j.cmet.2025.11.001.
Iyassu K Sebhat 1,  Monika J M Murphy 1,  Shuqin Zheng 1,  Robert J Lovelett 1,  Maja Engelstoft 1,  Daniel Kosinski 1,  Xiaodong Yang 1,  Victoria Dunn 1,  John Whang 1,  Maximilian G Lombardo 1,  Adrian Heilbut 2,  Giuseppe Terracina 1,  Nicole Nicholas 1,  Molly Leitner 1,  Matthew J Consolati 1,  Bryan Chan 1,  Gregory Poterewicz 1,  Annemarie Vance 1,  Jiajun Liu 1,  Ann E Weber 1,  Brett Lauring 1,  Nancy Thornberry 1,  Shirly Pinto 3
Affiliations

Affiliations

  • 1 Kallyope, Inc., New York, NY 10016, USA.
  • 2 New York, NY, USA.
  • 3 Kallyope, Inc., New York, NY 10016, USA. Electronic address: [email protected].
PMID: 41338185 DOI: 10.1016/j.cmet.2025.11.001
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.

Keywords

CCK; GLP-1; GPR119; GPR40; PYY; bariatric surgery; enteroendocrine cells; glucose control; gut enteroids; gut peptides; obesity; single-cell sequencing; weight loss.

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