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.