Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion
| Autor: | Shijun Yan, Jason M. Conley, Austin M. Reilly, Natalie D. Stull, Surabhi D. Abhyankar, Aaron C. Ericsson, Tatsuyoshi Kono, Andrei I. Molosh, Chandrashekhar A. Kubal, Carmella Evans-Molina, Hongxia Ren |
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| Rok vydání: | 2022 |
| Předmět: |
Blood Glucose
Male Enteroendocrine Cells Nerve Tissue Proteins Gastric Inhibitory Polypeptide Incretins General Biochemistry Genetics and Molecular Biology Cell Line Receptors G-Protein-Coupled Receptors Gastrointestinal Hormone Mice Glucagon-Like Peptide 1 Insulin Secretion Cyclic AMP Diabetes Mellitus Animals Humans Insulin Obesity Intestinal Mucosa Mice Knockout Glucose Tolerance Test Glucose HEK293 Cells Calcium Female HeLa Cells |
| Zdroj: | Cell Reports. 38:110179 |
| ISSN: | 2211-1247 |
| Popis: | G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention. |
| Databáze: | OpenAIRE |
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