Regulator of G-protein signaling expression in human intestinal enteroendocrine cells and potential role in satiety hormone secretion in health and obesityResearch in context

• Published in: EBioMedicine Vol. 107; p. 105283
• Main Authors: Alison N. McRae, Alexander L. Ticho, Yuanhang Liu, Maria Laura Ricardo-Silgado, Nothando N. Mangena, Fauzi Feris Jassir, Daniel Gonzalez-Izundegui, Gerardo Calderon, Fariborz Rakhshan Rohakhtar, Vernadette Simon, Ying Li, Cadman Leggett, Daniela Hurtado, Nicholas LaRusso, Andres J. Acosta
• Format: Journal Article
• Language: English
• Published: Elsevier 01-09-2024
• Subjects: Enteroendocrine cells; GLP-1; L-cells; Obesity; PYY; scRNA-Seq
• ISSN: 2352-3964

Background: Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown. Methods: Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients’ postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI–H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion. Findings: Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI–H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion. Interpretation: This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs. Funding: AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.