Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Selective release of gastrointestinal hormones induced by an orally active GPR39 agonist

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  1. Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  2. Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  • Kaare V Grunddal
  • Thi A Diep
  • Natalia Petersen
  • Iain R Tough
  • Louise J Skov
  • Lingzhi Liu
  • Jesse A Buijink
  • Franziska Mende
  • Chunyu Jin
  • Sara L Jepsen
  • Louis M E Sørensen
  • Michael P Achiam
  • Rune B Strandby
  • Anders Bach
  • Bolette Hartmann
  • Thomas M Frimurer
  • Siv A Hjorth
  • Michel Bouvier
  • Helen Cox
  • Birgitte Holst
Vis graf over relationer

OBJECTIVES: Obesity is a complex disease associated with a high risk of comorbidities. Gastric bypass surgery, an invasive procedure with low patient eligibility, is currently the most effective intervention that achieves sustained weight loss. This beneficial effect is attributed to alterations in gut hormone signaling. An attractive alternative is to pharmacologically mimic the effects of bariatric surgery by targeting several gut hormonal axes. The G protein-coupled receptor 39 (GPR39) expressed in the gastrointestinal tract has been shown to mediate ghrelin signaling and control appetite, food intake, and energy homeostasis, but the broader effect on gut hormones is largely unknown. A potent and efficacious GPR39 agonist (Cpd1324) was recently discovered, but the in vivo function was not addressed. Herein we studied the efficacy of the GPR39 agonist, Cpd1324, on metabolism and gut hormone secretion.

METHODS: Body weight, food intake, and energy expenditure in GPR39 agonist-treated mice and GPR39 KO mice were studied in calorimetric cages. Plasma ghrelin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) levels were measured. Organoids generated from murine and human small intestine and mouse colon were used to study GLP-1 and PYY release. Upon GPR39 agonist administration, dynamic changes in intracellular GLP-1 content were studied via immunostaining and changes in ion transport across colonic mucosa were monitored in Ussing chambers. The G protein activation underlying GPR39-mediated selective release of gut hormones was studied using bioluminescence resonance energy transfer biosensors.

RESULTS: The GPR39 KO mice displayed a significantly increased food intake without corresponding increases in respiratory exchange ratios or energy expenditure. Oral administration of a GPR39 agonist induced an acute decrease in food intake and subsequent weight loss in high-fat diet (HFD)-fed mice without affecting their energy expenditure. The tool compound, Cpd1324, increased GLP-1 secretion in the mice as well as in mouse and human intestinal organoids, but not in GPR39 KO mouse organoids. In contrast, the GPR39 agonist had no effect on PYY or GIP secretion. Transepithelial ion transport was acutely affected by GPR39 agonism in a GLP-1- and calcitonin gene-related peptide (CGRP)-dependent manner. Analysis of Cpd1324 signaling properties showed activation of Gαq and Gαi/o signaling pathways in L cells, but not Gαs signaling.

CONCLUSIONS: The GPR39 agonist described in this study can potentially be used by oral administration as a weight-lowering agent due to its stimulatory effect on GLP-1 secretion, which is most likely mediated through a unique activation of Gα subunits. Thus, GPR39 agonism may represent a novel approach to effectively treat obesity through selective modulation of gastrointestinal hormonal axes.

OriginalsprogEngelsk
Artikelnummer101207
TidsskriftMolecular Metabolism
Vol/bind49
ISSN2212-8778
DOI
StatusUdgivet - jul. 2021

Bibliografisk note

Copyright © 2021. Published by Elsevier GmbH.

ID: 73910783