Insulin Resistance in Macrophages Alters Their Metabolism and Promotes an M2-Like Phenotype

Area of Science:

• Immunometabolism
• Macrophage Biology
• Metabolic Disorders

Background:

• Obesity and insulin resistance profoundly impact cellular metabolism.
• The specific effects of insulin resistance on macrophage metabolism remain largely uncharacterized.
• Understanding these effects is crucial for metabolic and immune health.

Purpose of the Study:

• To investigate how chronic insulin exposure and insulin resistance affect macrophage metabolism and function.
• To characterize the phenotype and metabolic profile of insulin-resistant macrophages.
• To explore the implications of insulin-resistant macrophages in the context of sepsis.

Main Methods:

• Macrophages were chronically exposed to insulin in vitro and in vivo in diet-induced obese mice.
• Insulin signaling pathways (Akt2 phosphorylation) and mTORC1 activity were assessed.
• Macrophage phenotypes (M2-like) and responses to lipopolysaccharide (LPS) were evaluated.
• Glycolysis and gene expression of glycolytic enzymes were measured.
• The role of mTORC1 inhibition was examined.
• Sepsis-induced lung injury was assessed in mice with insulin-resistant macrophages.

Main Results:

• Chronic insulin exposure induced insulin resistance in macrophages, evidenced by impaired Akt2 phosphorylation.
• Insulin-resistant macrophages exhibited elevated basal mTORC1 activity and an M2-like phenotype.
• These macrophages showed reduced responses to LPS but increased glycolysis and glycolytic enzyme expression.
• Inhibition of mTORC1 reversed the M2-like phenotype and suppressed glycolysis.
• Mice with insulin-resistant macrophages showed reduced lung injury during polymicrobial sepsis.

Conclusions:

• Macrophages can develop insulin resistance, characterized by increased glycolysis and an M2-like phenotype (termed M-insulin resistant).
• This M-insulin resistant state is linked to obesity-related changes in macrophage function and trained immunity.
• Insulin-resistant macrophages may confer protection against sepsis-induced lung injury.