GLP-1 Is Not Enough: Can Glucagon Fill the Energy Expenditure Gap?

Obesity results from an imbalance between energy intake and energy expenditure (EE). Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce weight through appetite suppression but exert minimal influence on EE, potentially limiting long-term efficacy due to adaptive declines in metabolic rate. In contrast, glucagon, traditionally regarded as a glucose counter-regulatory hormone, has emerged as a potent catabolic signal with actions on lipid oxidation, substrate mobilization, and EE. These properties position glucagon receptor (GCGR) agonists as complements to GLP-1R agonism, with the potential to close the EE gap in obesity pharmacotherapy.

This review examines glucagon as an endocrine regulator of EE, integrating evidence from historical, preclinical, and clinical studies. Preclinical models demonstrate that glucagon increases oxygen consumption, stimulate brown adipose tissue, and promote endocrine pathways including fibroblast growth factor 21 (FGF21), a hepatokine that increases EE by enhancing lipid oxidation and thermogenic gene programs. Human studies reveal modest and context-dependent effects, with glucagon administration increasing EE in fasted or insulin-deficient states, whereas the response is attenuated postprandially or under hyperinsulinemia. This translational gap highlights the complexity of glucagon biology and the challenges of leveraging it therapeutically. Nevertheless, GLP-1R/GCGR co-agonism has demonstrated superior weight-loss efficacy in clinical trials and is advancing toward clinical application.

Glucagon may complement the appetite-suppressing effects of GLP-1 by engaging metabolic pathways that promote catabolism and EE. While preclinical evidence is strong, human data remain limited and context dependent. Further work is needed to elucidate the mechanisms of emerging GLP-1R/GCGR co-agonists and to determine whether combining appetite suppression with the catabolic effects of glucagon can achieve durable, lean mass-sparing weight loss in people living with obesity.