Glucagon controls obesity-specific energy expenditure via persistent cAMP/PKA signaling.

BACKGROUND & AIMS: Glucagon (GCG) analogues are gaining attention as promising components in incretin-based therapeutics for obesity and metabolic dysfunction-associated steatohepatitis. However, the biology of chronic glucagon treatment, particularly the molecular underpinnings of GCG-induced energy expenditure and lipid metabolism, remains poorly defined.

METHODS

We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor knockout mouse models. Through an integrative approach that combined metabolic, biochemical, and omics techniques, we investigated the molecular mechanisms underlying GCG-induced energy expenditure and metabolic benefits.

RESULTS

We demonstrate that the LA-GCG enhances energy expenditure in diet-induced obese mice with an essential role of hepatic, but not adipose, glucagon receptor (GCGR) signaling. Intriguingly, the enhancement in energy expenditure is observed only in obese but not in lean mice. The preferential efficacy is plausibly found in a prolonged activation of cAMP/PKA signaling through PDE4B/4D downregulation by LA-GCG. Conversely, the cAMP/PKA signaling is promptly attenuated by the PDE4B/4D activity in lean mice. Interestingly, unlike the EE phenotype, the lipid-clearing capacity of LA-GCG is independent of the PDE4/cAMP/PKA axis.

CONCLUSIONS

These findings provide the molecular basis for GCG-induced energy expenditure and metabolic benefits and suggest the phenotypic segregation of cAMP/PKA-dependent and independent effects.

IMPACT AND IMPLICATIONS

This study provides fundamental mechanistic insights into GCG pharmacology with direct clinical implications. The obesity-specific enhancement of energy expenditure by GCGR agonist substantiates the superior efficacy of GCGR/glucagon-like peptide-1 receptor (GLP-1R) dual agonists in individuals with obesity compared to GLP-1R mono-agonists. Importantly, differential PDE4 expression patterns may provide a molecular basis for the variable weight-loss responses to GCG-based agonists, identifying PDE4 inhibition as a potential strategy to restore efficacy in GCG-non-responders. Furthermore, the PDE4-overexpression model preserved the lipid-clearing capacity of GCGR agonist while attenuating hyperglycemic risk, demonstrating a translatable strategy to optimize the safety-efficacy profile of GCG-based therapies for cardio-renal-metabolic diseases such as obesity and MASH.