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.
Highlights
Role of CCAAT/enhancer-binding protein  in obesity-induced inflammation remains unexplored
The F4/80ϩ ATM staining was highly concentrated in the nuclei of WT high fat diet (HFD)-fed mice, while this staining was absent in CCAAT/enhancer-binding protein  (C/EBP)Ϫ/Ϫ mice on CON or HFD, suggestive of less tissue macrophage content
In the present study we demonstrate using both gain- and loss-of-function approaches in RAW 264.7 macrophages, peritoneal macrophages (PM) cells, and in mice lacking CCAAT/enhancer-binding protein (C/EBP) in bone marrow-derived cells that C/EBP is required for lipid-induced inflammatory responses and the activation of the innate immune system in response to HFD
Summary
Role of CCAAT/enhancer-binding protein  in obesity-induced inflammation remains unexplored. 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. 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. Signaling pathways within macrophages, including TLR4 [12], IKK [13], JNK1 [14], Cbl-associated protein [15], and fatty acid-binding protein/AP2 [16], or overexpression of diacylglycerol acyltransferase (DGAT) 1 in macrophages [17], resulted in loss of monocyte migration and protected obese mice from inflammation and insulin resistance while on a HFD. On the basis of these results, we discuss how accumulation of C/EBP in macrophage and adipose tissue plays a direct role in the molecular pathway(s) for initiation of fatty acid-induced inflammation and the pathogenesis of obesity-linked insulin resistance
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