Glucagon controls obesity-specific energy expenditure via persistent cAMP/PKA signaling
This study provides fundamental mechanistic insights into GCG pharmacology, which has direct clinical relevance. The obesity-specific enhancement of energy expenditure by GCGR agonism supports the superior efficacy of GCGR/glucagon-like peptide-1 receptor (GLP-1R) dual agonists over GLP-1R mono-agonists in individuals with obesity. Importantly, differential expression patterns of PDE4 may underlie variability in weight loss responses to GCG-based therapies, identifying PDE4 inhibition as a potential strategy to restore efficacy in GCG non-responders. Moreover, a PDE4-overexpression model preserved the lipid-clearing effects of GCGR agonism while attenuating hyperglycemic risk, offering a translatable approach to optimize the safety-efficacy profile of GCG-based treatments for cardio-renal-metabolic diseases, including obesity and metabolic dysfunction-associated steatohepatitis.
Authors
- Adhideb Ghosh (ORCID: https://orcid.org/0000-0002-5160-4571)
- Lianggong Ding (ORCID: https://orcid.org/0000-0001-9385-7799)
- Marcus Höring (ORCID: https://orcid.org/0000-0002-3651-392X)
- Christian Wolfrum (ORCID: https://orcid.org/0000-0002-3862-6805)
- Benjamin Strobel (ORCID: https://orcid.org/0000-0002-8687-3499)
- Falko Noé (ORCID: https://orcid.org/0009-0002-3360-5455)
- Wolfgang Rist (ORCID: https://orcid.org/0000-0002-0626-3544)
- Gerhard Liebisch (ORCID: https://orcid.org/0000-0003-4886-0811)
- Fen Long
- Anton Pekcec (ORCID: https://orcid.org/0000-0001-9045-4740)
- Anand K. Sharma (ORCID: https://orcid.org/0000-0001-7532-5983)
- Heike Neubauer (ORCID: https://orcid.org/0000-0001-8470-968X)
- Tenagne D. Challa (ORCID: https://orcid.org/0000-0002-5898-8061)
- Manuel Klug
- Chunyan Wu
- Tongtong Wang (ORCID: https://orcid.org/0000-0002-8807-2441)
- Mafalda Maria Azevedo Pereira (ORCID: https://orcid.org/0000-0002-7913-847X)
- Tina Zimmermann
- Carla Horvath
Institutions
- Boehringer Ingelheim (Germany) (DE)
- University Hospital Regensburg (DE)
- ETH Zurich (CH)
- Nutrition Sciences (Belgium) (BE)
Publication Details
- Journal
- Journal of Hepatology
- Published
- 2025-06-21
- DOI
- https://doi.org/10.1016/j.jhep.2025.06.011
- Citations
- 10
- Primary Topic
- Diabetes Treatment and Management
- Type
- article
- Field-Weighted Citation Impact
- 12.95
Funders
- Boehringer Ingelheim
- Eidgenössische Technische Hochschule Zürich
- Universität Zürich
- Functional Genomics Center Zurich