Estrogenic activity of E2-conjugated GLP-1 is mediated by intracellular endolysosomal acidification and estrone metabolism
Together, our data suggest that GLP-1-CEX/E2 depends on GLP-1R trafficking and lysosome acidification for estrogenic efficacy, with a likely conversion of the liberated E2-3-ether metabolite into estrone-3-sulfate, resulting in a residual downstream flux into active estradiol. Our current findings aim to improve the understanding of small molecule targeting and the efficacy behind GLP-1/small molecule conjugates.
Authors
- Matthias Tschoep (ORCID: https://orcid.org/0000-0002-4744-371X)
- Jonathan D. Douros (ORCID: https://orcid.org/0000-0003-2299-6163)
- Daniela Liśkiewicz (ORCID: https://orcid.org/0000-0002-5859-6316)
- Callum Coupland (ORCID: https://orcid.org/0000-0001-8921-3616)
- Patrick J. Knerr
- Bin Yang (ORCID: https://orcid.org/0000-0003-4748-2484)
- Gandhari Maity
- Aaron Novikoff (ORCID: https://orcid.org/0000-0002-4838-001X)
- Arkadiusz Liśkiewicz (ORCID: https://orcid.org/0000-0002-4102-5373)
- Brian Finan (ORCID: https://orcid.org/0000-0002-6467-0447)
- Timo D. Müller (ORCID: https://orcid.org/0000-0002-0624-9339)
- Richard D. DiMarchi (ORCID: https://orcid.org/0000-0003-0220-4085)
- Seun Akindehin (ORCID: https://orcid.org/0000-0002-6557-0843)
- Axel Walch (ORCID: https://orcid.org/0000-0001-5578-4023)
- Ahmed Khalil (ORCID: https://orcid.org/0000-0002-3302-6253)
- Gerald Grandl (ORCID: https://orcid.org/0000-0003-4456-1988)
- Na Sun (ORCID: https://orcid.org/0009-0007-9151-2456)
- Özüm Ezgi Karaoglu
Institutions
- Eli Lilly (United States) (US)
- Indiana Biosciences Research Institute (US)
- Helmholtz Zentrum München (DE)
- Novo Nordisk (United States) (US)
- Indiana University Bloomington (US)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Molecular Metabolism
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1016/j.molmet.2025.102136
- Citations
- 3
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.35
Funders
- Deutsche Forschungsgemeinschaft
- H2020 European Research Council