Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice

Dawood Khan, Opeolu O. Ojo, Orla RM Woodward, Jo Edward Lewis, Ananyaa Sridhar, Fiona M. Gribble, Frank Reimann, Peter R. Flatt, R. Charlotte Moffett, Stanley M Hileman (Editor), Thomas R. Caulfield (Editor)

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Abstract

Substantial evidence suggests crosstalk between reproductive and gut-axis but mechanisms linking metabolism and reproduction are still unclear. The present study evaluated the possible role of glucose-dependent-insulinotropic-polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) in reproductive function by examining receptor distribution and the effects of global GIPR and GLP-1R deletion on estrous cycling and reproductive outcomes in mice. GIPR and GLP-1R gene expression were readily detected by PCR in female reproductive tissues including pituitary, ovaries and uterine horn. Protein expression was confirmed with histological visualisation of incretin receptors using GIPR-Cre and GLP1R-Cre mice in which the incretin receptor expressing cells were fluorescently tagged. Functional studies revealed that female GIPR −/− and GLP-1R −/− null mice exhibited significantly (p < 0.05 and p < 0.01) deranged estrous cycling compared to wild-type controls, indicative of reduced fertility. Furthermore, only 50% and 16% of female GIPR −/− and GLP-1R −/− mice, respectively produced litters with wild-type males across three breeding cycles. Consistent with a physiological role of incretin receptors in pregnancy outcome, litter size was significantly (p < 0.001–p < 0.05) decreased in GIPR −/− and GLP-1R −/− mice. Treatment with oral metformin (300 mg/kg body-weight), an agent used clinically for treatment of PCOS, for a further two breeding periods showed no amelioration of pregnancy outcome except that litter size in the GIPR −/− group was approximately 2 times greater in the second breeding cycle. These data highlight the significance of incretin receptors in modulation of female reproductive function which may provide future targets for pharmacological intervention in reproductive disorders.

Original languageEnglish
Article number1736
Number of pages13
JournalBiomolecules
Volume12
Issue number12
Early online date23 Nov 2022
DOIs
Publication statusPublished (in print/issue) - 23 Nov 2022

Bibliographical note

Funding Information:
These studies were supported by Diabetes UK RDLF grant to RCM and Ulster University strategic funding. Research in the laboratory of FMG and FR is supported by the MRC (MRC_MC_UU_12012/3) and Wellcome Trust (220271/Z/20/Z). ORMW Jensis supported by a BBSRC iCASE PhD studentship partnered with AstraZeneca.

Publisher Copyright:
© 2022 by the authors.

Keywords

  • Incretins
  • GLP-1R
  • GIPR
  • PCOS
  • fertility
  • Glucagon-Like Peptide 1/metabolism
  • Receptors, G-Protein-Coupled
  • Male
  • Glucagon-Like Peptide-1 Receptor/genetics
  • Pregnancy
  • Animals
  • Gastric Inhibitory Polypeptide/metabolism
  • Female
  • Mice
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Gipr
  • Glp-1r
  • Reproduction
  • Glucagon-Like Peptide-1 Receptor
  • Fertility
  • Pregnancy Outcome

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