C/EBPα regulates macrophage activation and systemic metabolism

Abstract

/EBP␣ regulates macrophage activation and systemic metabolism. Am J Physiol Endocrinol Metab 306: E1144 -E1154, 2014. First published April 1, 2014; doi:10.1152/ajpendo.00002.2014.-Macrophage infiltration plays an important role in obesity-induced insulin resistance. CCAAT enhancerbinding protein-␣ (C/EBP␣) is a transcription factor that is highly expressed in macrophages. To examine the roles of C/EBP␣ in regulating macrophage functions and energy homeostasis, macrophage-specific C/EBP␣ knockout (M␣KO) mice were created. Chowfed M␣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␣KO mice, systemic insulin sensitivity was protected during HFfeeding due to preserved insulin sensitivity in skeletal muscle. We also found that C/EBP␣-deficient macrophages exhibited a blunted response of cytokine-induced expression of M1 and M2 macrophage markers, suggesting that C/EBP␣ 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␣KO mice. Furthermore, expression levels of inflammatory cytokines were reduced in skeletal muscle of HF-fed M␣KO mice. Together, these results imply that C/EBP␣ is required for macrophage activation, which plays an important role in maintaining skeletal muscle energy metabolism.CCAAT/enhancer binding protein; insulin sensitivity; obesity; macrophage MACROPHAGES ARE RESIDENT IMMUNE CELLS found in nearly all tissues (23). Obesity increases macrophage infiltration in white adipose tissue (WAT) and other tissues (14,17,22,29,30). In addition, macrophages recruited under conditions of obesity appear to be more inflammatory (M1 macrophages), and this leads to reduced insulin sensitivity and glucose metabolism (16,26,29). However, under physiological conditions, tissue macrophages are also important in maintaining metabolic homeostasis and tissue structure as they appear to play an antiinflammatory role (M2 macrophages) (25,27). For example, macrophage PPAR␥ deficiency leads to impaired insulin sensitivity in skeletal muscle and liver of chow-fed mice (13). Therefore, macrophages may play distinct roles between lean and obese conditions, either maintaining or impairing metabolism. However, the mechanism underlying the shift of macrophage functions between lean and obese conditions is unknown. C/EBP␣ is the prototypical member of the C/EBP transcription factor family, which comprises six members (␣-). C/EBP proteins are widely expressed and regulate a variety of cellular and physiological processes, including energy metabolism, immunity, inflammation, hematopoiesis, and adipogenesis (3,4,7,10,35). C/EBP␣ is highly expressed in early myeloid progenitors and may regulate monocyte and macrophage development (10 -12, 40). However, the r...

JUNB Is a Key Transcriptional Modulator of Macrophage Activation

“…The defects we observed in JUNB-deficient macrophages included altered transcription of a subset of immune-related genes, decreased secretion of M(LPS)-associated cytokines in response to TLR ligands, and weakened M(IL-4) polarization following treatment with IL-4. It is notable that JUNB positively regulates both M(LPS) and M(IL-4) activation, since to our knowledge, virtually all previously described transcription factors with demonstrated roles in macrophage polarization specifically promote either M(LPS) or M(IL-4) activation, with the exception of C/EBPα (38). Importantly, at baseline, Junb Δ Lyz2 mice exhibit no gross defects in survival or development, suggesting that deletion of JUNB does not disrupt the homeostatic functions of monocytes and tissue macrophages but specifically affects activation.…”

Metabolic benefits of curcumin supplementation in patients with metabolic syndrome: A systematic review and meta‐analysis of randomized controlled trials

“…The expression of PPARγ and C/EBPα in mice and in adipocytes (3T3‐L1 cells) by curcumin improved insulin resistance, glucose uptake (Pan et al, ), lipolysis of circulating TGs, and their storage in adipose tissue (Kim et al, ; B. Lee et al, ). But a dose of curcumin is important for upregulating the protein expression of PPARγ and C/EBPα in adipocytes, and a high dose of curcumin was ineffective in the adipocyte (Pan et al, ).…”

Progranulin Controls Sepsis via C/EBPα-RegulatedIl10Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation

“…Kang and colleagues found that IL-32 induced IL-10 expression by suppressing C/EBPαbinding to IL-10 promoter and suggested that C/EBPα DNA binding negatively regulates IL-10 expression (43). In a recent study using a myeloid specific C/EBPαknockout model, Lee and coworkers showed that in C/EBPα-deficient macrophages, IL-10 levels were reduced in response to M2 differentiation stimulus IL-4, but were unchanged in white fat tissue, as compared to wild type counterparts (77), suggesting tissue-specific and differential ways of regulation of IL-10 by C/EBPα.…”