CCAAT/enhancer-binding protein β (C/EBPβ) expression regulates dietary-induced inflammation in macrophages and adipose tissue in mice.

Abstract

Strong evidence exists for a link between chronic low level inflammation and dietary-induced insulin resistance; however, little is known about the transcriptional networks involved. Here we show that high fat diet (HFD) or saturated fatty acid exposure directly activates CCAAT/enhancer-binding protein β (C/EBPβ) protein expression in liver, adipocytes, and macrophages. Global C/EBPβ deletion prevented HFD-induced inflammation and surprisingly increased mitochondrial gene expression in white adipose tissue along with brown adipose tissue markers PRDM16, CIDEa, and UCP1, consistent with a resistance to HFD-induced obesity. In isolated peritoneal macrophages from C/EBPβ(-/-) mice, the anti-inflammatory gene LXRα and its targets SCD1 and DGAT2 were strikingly up-regulated along with IL-10, while NLRP3, a gene important for activating the inflammasome, was suppressed in response to palmitate. Using RAW 264.7 macrophage cells or 3T3-L1 adipocytes, C/EBPβ knockdown prevented palmitate-induced inflammation and p65-NFκB DNA binding activity, while C/EBPβ overexpression induced NFκB binding, JNK activation, and pro-inflammatory cytokine gene expression directly. Finally, chimeric bone marrow mice transplanted with bone marrow lacking C/EBPβ(-/-) demonstrated reduced systemic and adipose tissue inflammatory markers, macrophage content, and maintained insulin sensitivity on HFD. Taken together, these results demonstrate that HFD or palmitate exposure triggers C/EBPβ expression that controls expression of distinct aspects of alternative macrophage activation. Reducing C/EBPβ in macrophages confers protection from HFD-induced systemic inflammation and insulin resistance, suggesting it may be an attractive therapeutic target for ameliorating obesity-induced inflammatory responses.

• Authors: Shaikh M Rahman, Rachel C Janssen, Mahua Choudhury, Karalee C Baquero, Rebecca M Aikens, Becky A de la Houssaye, Jacob E Friedman
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 41 Pg. 34349-60 (Oct 05 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22902781 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation
• CCAAT-Enhancer-Binding Protein-beta
• Carrier Proteins
• Cebpb protein, mouse
• Dietary Fats
• IL10 protein, mouse
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Rela protein, mouse
• Transcription Factor RelA
• Interleukin-10
• MAP Kinase Kinase 4

Topics

• 3T3-L1 Cells
• Adipose Tissue, Brown (metabolism, pathology)
• Animals
• Antigens, Differentiation (genetics, metabolism)
• CCAAT-Enhancer-Binding Protein-beta (biosynthesis, genetics)
• Carrier Proteins (genetics, metabolism)
• Dietary Fats (adverse effects, pharmacology)
• Enzyme Activation (drug effects, genetics)
• Gene Expression Regulation (drug effects)
• Inflammasomes (genetics, metabolism)
• Inflammation (genetics, metabolism, pathology)
• Interleukin-10 (genetics, metabolism)
• MAP Kinase Kinase 4 (genetics, metabolism)
• Macrophage Activation (drug effects, genetics)
• Macrophages (metabolism, pathology)
• Mice
• Mice, Knockout
• Mitochondria (genetics, metabolism, pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Obesity (chemically induced, genetics, metabolism, pathology)
• Transcription Factor RelA (genetics, metabolism)