Hepatic glucagon action: beyond glucose mobilization

Area of Science:

• Endocrinology
• Metabolic Diseases
• Hepatology

Background:

• Glucagon has long been recognized for promoting hepatic glucose production and was historically viewed as a diabetogenic agent.
• Traditionally considered insulin's counter-regulatory hormone, glucagon's multifaceted roles in metabolic regulation are increasingly appreciated.
• New 'omics' technologies are revealing glucagon's broader impact beyond glucose homeostasis.

Purpose of the Study:

• To explore the expanding functions of glucagon signaling within hepatocytes.
• To challenge the conventional view of glucagon solely as a catabolic hormone.
• To highlight glucagon's potential as a therapeutic target for metabolic dysfunction-associated steatotic disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), obesity, and chronic kidney disease.

Main Methods:

• Review of current scientific literature and emerging evidence on glucagon signaling.
• Analysis of 'omics' data implicating glucagon in diverse metabolic pathways.
• Examination of glucagon's role in hepatic lipid, amino acid, and ketone body metabolism.

Main Results:

• Glucagon enhances fatty acid oxidation and reduces endogenous lipid synthesis, demonstrating a dichotomous metabolic role.
• Glucagon influences hepatic amino acid and ketone body metabolism, as well as mitochondrial function.
• Glucagon receptor agonism, balanced with incretins like glucagon-like peptide 1 (GLP-1), is a promising therapeutic strategy.

Conclusions:

• Glucagon's functions extend beyond glucose regulation, impacting lipid, amino acid, and mitochondrial metabolism.
• The traditional view of glucagon as purely catabolic is incomplete; it plays complex regulatory roles in metabolic homeostasis.
• Understanding these broader roles opens new avenues for treating metabolic diseases like MASLD/MASH.