IRF3 promotes adipose inflammation and insulin resistance and represses browning

Kumari, Manju; Wang, Xun; Lantier, Louise; Lyubetskaya, Anna; Eguchi, Jun; Kang, Sona; Tenen, Danielle; Roh, Hyun Cheol; Kong, Xingxing; Kazak, Lawrence; Ahmad, Rasheed; Rosen, Evan D.

doi:10.1172/jci86080

Cited by 153 publications

(149 citation statements)

References 63 publications

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“…Our motif enrichment analysis identified NFKB1 as one of the motifs enriched in the peaks that were up-regulated in vivo b ut down-regulated in cultured adipocytes. Together with previous reports that the NFκB pathway is resistant to lipopolysaccharide (LPS) stimulation in 3T3-L1 adipocytes (Berg et al, 2004; Kumari et al, 2016), these results suggest that the NFκB-mediated inflammatory pathway may act differently in vivo compared to in vitro . Additionally, we found that cell cycle-related pathways were enriched in 3T3-L1 adipocytes compared to in vivo adipocytes, consistent with the proliferative potential of immortalized cells generally and the known reliance of 3T3-L1 cells on mitotic clonal expansion prior to differentiation (Cristancho and Lazar, 2011).…”

Section: Discussionsupporting

confidence: 83%

Simultaneous Transcriptional and Epigenomic Profiling from Specific Cell Types within Heterogeneous Tissues In Vivo

et al. 2017

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SUMMARY Epigenomic mechanisms direct distinct gene expression programs for different cell types. Various in vivo tissues have been subjected to epigenomic analysis; however, these studies have been limited by cellular heterogeneity resulting in composite gene expression and epigenomic profiles. Here, we introduce “NuTRAP”, a transgenic mouse that allows simultaneous isolation of cell type-specific translating mRNA and chromatin from complex tissues. Using NuTRAP, we successfully characterize gene expression and epigenomic states of various adipocyte populations in vivo, revealing significant differences compared to either whole adipose tissue or in vitro adipocyte cell lines. We find that ChIP-seq using NuTRAP is highly efficient, scalable, and robust with even limited cell input. We further demonstrate the general utility of NuTRAP by analyzing hepatocyte-specific epigenomic states. The NuTRAP mouse is a resource that provides a powerful system for cell type-specific gene expression and epigenomic profiling.

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Section: Discussionsupporting

confidence: 83%

Simultaneous Transcriptional and Epigenomic Profiling from Specific Cell Types within Heterogeneous Tissues In Vivo

et al. 2017

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“…Third, we show that poly I:C mediated phosphorylation/activation of IRF3 mimics the effect of palmitate in the cooperative actions on CCL2 secretion. We also show that palmitate leads to phosphorylation of IRF3, like other upstream activators such as poly I:C or LPS(60). Fourth, IRF3-deficient cells failed to respond synergistically to palmitate and TNF-α co-stimulation.…”

Section: Discussionmentioning

confidence: 61%

The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation

Ahmad

Al-Roub

Kochumon

et al. 2018

The Journal of Immunology

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The chemokine CCL2 (also known as MCP-1) is a key regulator of monocyte infiltration into adipose tissue, which plays a central role in the pathophysiology of obesity-associated inflammation and insulin resistance. It remains unclear how CCL2 production is upregulated in obese humans and rodents. Because elevated levels of the free fatty acid (FFA) palmitate and TNF-α have been reported in obesity, we studied whether these agents interact to trigger CCL2 production. Our data show that combined treatment of THP-1 and primary human monocytic cells with palmitate and TNF-α led to a marked increase in CCL2 production compared to either treatment alone. Mechanistically, we found that cooperative production of CCL2 by palmitate and TNF-α did not require MyD88, but was attenuated by blocking TLR4 or TRIF. IRF3-deficient cells did not show synergistic CCL2 production in response to palmitate/TNF-α. Moreover, IRF3 activation by poly I:C augmented TNF-α induced CCL2 secretion. Interestingly, elevated NF-κB/AP-1 activity resulting from palmitate/TNF-α co-stimulation was attenuated by TRIF/IRF3 inhibition. Diet-induced C57BL/6 obese mice with high FFAs levels showed strong correlation between TNF-α and CCL2 in plasma and adipose tissue and, as expected, also showed increased adipose tissue macrophage accumulation compared to lean mice. Similar results were observed in the adipose tissue samples from obese humans. Overall, our findings support a model in which elevated FFAs in obesity create a milieu for TNF-α to trigger CCL2 production via the TLR4/TRIF/IRF3 signaling cascade, representing a potential contribution of FFAs to metabolic inflammation.

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“…Work in the aorta has shown that palmitate blocked insulin signal transduction, which was blocked in TLR4 knockout mice [12]. Using interferon regulatory factor 3 (IRF3) knockout mice, work showed that these mice are protected against obesity through decreased TLR4 signaling [21]. In contrast to work on the aorta and insulin responsive organs, a study did show that TLR4 is protective to cardiomyocytes, producing decreased apoptosis through iNOS and MyD88 [11].…”

Section: 0 Discussionmentioning

confidence: 99%

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

et al. 2017

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Objective and Design Work in multiple organs has suggested that toll-like receptor 4 (TLR4) may play a role in insulin resistance. Additional studies have shown a negative role for TLR4 on retinal health. We have previously reported that β-adrenergic receptors can regulate both TLR4 signal transduction, as well as insulin signaling in the retina and in retinal endothelial cells (REC). Thus, we hypothesized that TLR4 would regulate retinal insulin signaling. Materials and Methods We used endothelial cell specific TLR4 knockout mice, as well as TLR4 overexpressing mice for these studies. Methods Western blotting and ELISA analyses were done for investigations of insulin receptor, insulin receptor substrate 1 (IRS-1) serine 307, and Akt phosphorylation, as well as cleaved caspase 3 levels in the mouse retina. Results We found that loss of TLR4 led to increased insulin receptor and Akt phosphorylation, as well as decreased IRS-1Ser307 levels. In support of these results, TLR4 overexpression decreased insulin signaling and the cleavage of caspase 3. Conclusions Therefore, these results suggest that TLR4 plays a key role in insulin signaling in the retina. Reduction of TLR4 levels may be protective to the retina.

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IRF3 promotes adipose inflammation and insulin resistance and represses browning

Cited by 153 publications

References 63 publications

Simultaneous Transcriptional and Epigenomic Profiling from Specific Cell Types within Heterogeneous Tissues In Vivo

Simultaneous Transcriptional and Epigenomic Profiling from Specific Cell Types within Heterogeneous Tissues In Vivo

The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

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