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

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

We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor (GCGR) 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.

LA-GCG enhanced energy expenditure in diet-induced obese mice, with hepatic, but not adipose, GCGR signaling playing an essential role. Notably, this increase in energy expenditure was only observed in obese, not lean, mice. This preferential effect appeared to be mediated by sustained activation of cAMP/PKA signaling due to LA-GCG-induced downregulation of PDE4B/4D. In contrast, in lean mice, cAMP/PKA signaling is rapidly attenuated by PDE4B/4D activity. Interestingly, unlike energy expenditure, the lipid-clearing effects of LA-GCG were independent of the PDE4/cAMP/PKA axis.

These findings elucidate the molecular basis of GCG-induced energy expenditure and metabolic benefits, and highlight a phenotypic segregation between cAMP/PKA-dependent and -independent effects.

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.