The neglected PCK1/glucagon (inter)action in nutrient homeostasis beyond gluconeogenesis: disease pathogenesis and treatment

Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease. This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases. We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.