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

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.
AuthorsShaikh M Rahman, Rachel C Janssen, Mahua Choudhury, Karalee C Baquero, Rebecca M Aikens, Becky A de la Houssaye, Jacob E Friedman
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 41 Pg. 34349-60 (Oct 5 2012) ISSN: 1083-351X [Electronic] United States
PMID22902781 (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
  • CIAS1 protein, mouse
  • Carrier Proteins
  • Cebpb protein, mouse
  • Dietary Fats
  • IL10 protein, mouse
  • Inflammasomes
  • Rela protein, mouse
  • Transcription Factor RelA
  • Interleukin-10
  • MAP Kinase Kinase 4
  • 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)
  • Obesity (chemically induced, genetics, metabolism, pathology)
  • Transcription Factor RelA (genetics, metabolism)

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