C/EBPα regulates macrophage activation and systemic metabolism

Macrophage infiltration plays an important role in obesity-induced insulin resistance. CCAAT enhancer-binding protein-alpha (C/EBP alpha) is a transcription factor that is highly expressed in macrophages. To examine the roles of C/EBP alpha in regulating macrophage functions and energy homeostasis, macrophage-specific C/EBP alpha knockout (M alpha KO) mice were created. Chow-fed M alpha KO mice exhibited higher body fat mass and decreased energy expenditure despite no change in food intake. However, the obese phenotype disappeared after high-fat (HF) diet feeding. Although there was a transient decrease in insulin sensitivity of chow-fed young M alpha KO mice, systemic insulin sensitivity was protected during HF-feeding due to preserved insulin sensitivity in skeletal muscle. We also found that C/EBP alpha-deficient macrophages exhibited a blunted response of cytokine-induced expression of M1 and M2 macrophage markers, suggesting that C/EBP alpha controls both M1 and M2 polarization. Consistent with decreased exercise capacity, mitochondrial respiration rates and signal pathways for fatty acid oxidation were remarkably reduced in the skeletal muscle of chow-fed M alpha KO mice. Furthermore, expression levels of inflammatory cytokines were reduced in skeletal muscle of HF-fed M alpha KO mice. Together, these results imply that C/EBP alpha is required for macrophage activation, which plays an important role in maintaining skeletal muscle energy metabolism.