Itaconate potentiates hepatic gluconeogenesis through NRF2 induction.

Area of Science:

• Immunometabolism
• Liver Metabolism
• Glucose Homeostasis

Background:

• Systemic metabolism and immune responses significantly impact glucose homeostasis, particularly in diabetes and obesity.
• Immune metabolites mediate crosstalk, with itaconate (an inflammatory macrophage metabolite) emerging as a key player.
• Itaconate's role in glucose metabolism, especially in obesity, is recognized but poorly understood.

Purpose of the Study:

• To investigate the role of itaconate in liver glucose metabolism during fasting.
• To elucidate the molecular mechanisms by which itaconate influences gluconeogenesis.
• To determine the potential link between itaconate and metabolic-associated liver diseases.

Main Methods:

• Metabolite analysis in liver tissue under fasting and fed conditions.
• In vitro experiments assessing itaconate's effect on glucagon-induced gluconeogenesis.
• Gene expression analysis (gluconeogenic genes) under various conditions (basal, palmitic acid).
• Investigation of signaling pathways involved (insulin signaling, CREB, NRF2).

Main Results:

• Itaconate levels significantly increase in the liver during fasting.
• Itaconate enhances glucagon-induced liver gluconeogenesis independently of insulin signaling.
• Itaconate upregulates gluconeogenic gene expression via NRF2 activation, not CREB.
• Itaconate potentiates glucagon effects in the liver.

Conclusions:

• Itaconate enhances liver gluconeogenesis through NRF2 activation, independent of insulin signaling.
• Fasting-induced increases in itaconate may contribute to altered glucose metabolism.
• Itaconate's role in potentiating glucagon effects suggests its involvement in metabolic-associated liver diseases.