Immunometabolism of IRF4 in adipose, muscle, and immune cells influences obesity and MASLD

Interferon regulatory factor 4 (IRF4) connects immunity and metabolism in immune cells and parenchymal cells of metabolic tissues. In immune cells, IRF4 is a metabolic rheostat that promotes glycolysis to support macrophage polarization and increase oxidative phosphorylation to enable T cell proliferation and memory, while limiting transcription of pro-inflammatory programs. IRF4 also dictates cell-autonomous responses in adipocytes and muscle cells, including transcriptional regulation of lipolysis in white adipocytes, thermogenesis in brown adipocytes, and glucose and amino acid metabolism in muscle cells. IRF4 responds to nutritional status and hormonal signals involved in obesity pathogenesis and mediates interorgan communication involved in liver steatosis during metabolic dysfunction-associated steatotic liver disease (MASLD). This review summarizes how IRF4 participates in metabolic and immune responses in adipose tissue, skeletal muscle, liver, and tissue-resident immune cells during obesity. IRF4 immunometabolism is relevant to obesity and MASLD because of its bidirectional role in immune cells and metabolic cells. Obesity alters inflammatory and nutritional activators of IRF4, which modify immune and parenchymal cell metabolism to produce local and systemic metabolic inflammation, which can alter endocrine control of metabolism. Therefore, the cell-specific functions of IRF4 in immune cells and metabolic cells position IRF4 as a transcriptional node connecting changes in immunity and metabolism during metabolic disease.