Evidence for involvement of GIP and GLP-1 receptors and the gut-gonadal axis in regulating female reproductive function in mice
Authors
Khan, DawoodOjo, Opeolu
Woodward, Orla
Lewis, Jo Edward
Sridhar, Ananyaa
Gribble, Fiona
Reimann, Frank
Flatt, Peter
Moffett, R. Charlotte
Issue Date
2022-10-23
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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.Citation
Khan D, Ojo OO, Woodward OR, Lewis JE, Sridhar A, Gribble FM, Reimann F, Flatt PR, Moffett RC (2022) Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice. Biomolecules, 12(12):1736. https://doi.org/10.3390/biom12121736Publisher
MDPIJournal
BiomoleculesPubMed ID
36551163 (pubmed)Additional Links
https://www.mdpi.com/2218-273X/12/12/1736Type
Journal articleLanguage
enDescription
© 2022 The Authors. Published by MDPI. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.3390/biom12121736ISSN
2218-273XEISSN
2218-273XSponsors
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.ae974a485f413a2113503eed53cd6c53
10.3390/biom12121736
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Except where otherwise noted, this item's license is described as Licence for published version: Creative Commons Attribution 4.0 International
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