CCAAT/enhancer-binding protein (C/EBP) expression regulates dietary-induced inflammation in macrophages and adipose tissue in mice. Academic Article uri icon

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 (C/EBP) protein expression in liver, adipocytes, and macrophages. Global C/EBP 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/EBP(-/-) mice, the anti-inflammatory gene LXR 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/EBP knockdown prevented palmitate-induced inflammation and p65-NFB DNA binding activity, while C/EBP overexpression induced NFB binding, JNK activation, and pro-inflammatory cytokine gene expression directly. Finally, chimeric bone marrow mice transplanted with bone marrow lacking C/EBP(-/-) 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/EBP expression that controls expression of distinct aspects of alternative macrophage activation. Reducing C/EBP 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.

published proceedings

  • J Biol Chem

altmetric score

  • 3

author list (cited authors)

  • Rahman, S. M., Janssen, R. C., Choudhury, M., Baquero, K. C., Aikens, R. M., de la Houssaye, B. A., & Friedman, J. E.

citation count

  • 76

complete list of authors

  • Rahman, Shaikh M||Janssen, Rachel C||Choudhury, Mahua||Baquero, Karalee C||Aikens, Rebecca M||de la Houssaye, Becky A||Friedman, Jacob E

publication date

  • October 2012