Liver macrophages regulate systemic metabolism through non-inflammatory factors

Area of Science:

• Metabolic disease research
• Immunology
• Molecular biology

Background:

• Liver macrophages (LMs) were thought to drive metabolic disease via inflammation.
• Anti-inflammatory drugs offer limited benefits for systemic metabolism.

Purpose of the Study:

• To investigate the role of LMs in obesity-induced insulin resistance.
• To identify non-inflammatory mechanisms by which LMs affect liver metabolism.

Main Methods:

• Comparative analysis of LMs in flies, mice, and humans with varying metabolic states.
• Identification and functional characterization of LM-secreted factors.
• Investigation of RNA editing in IGFBP7 and its impact on insulin receptor binding.

Main Results:

• LMs do not exhibit a pro-inflammatory phenotype in obesity-induced insulin resistance.
• LMs secrete insulin-like growth factor-binding protein 7 (IGFBP7), which directly regulates liver lipogenesis and gluconeogenesis through ERK signaling.
• Increased RNA editing of IGFBP7 in insulin-resistant obese individuals enhances its insulin receptor binding capacity.

Conclusions:

• LMs contribute to insulin resistance independent of inflammation.
• Non-inflammatory factors like IGFBP7 secreted by LMs are critical regulators of metabolic homeostasis.
• IGFBP7 and its RNA editing present potential therapeutic targets for metabolic diseases.