Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance

Abstract

Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens. In HFD-fed mice, this excess of nucleic acids and related protein antigens worsens metabolic parameters through a number of mechanisms, including activation of VAT macrophages and expansion of plasmacytoid dendritic cells (pDCs) in the liver. Consistently, HFD-fed mice lacking critical responders of nucleic acid pathways, Toll-like receptors (TLR)7 and TLR9, show reduced metabolic inflammation and improved glucose homeostasis. Treatment of HFD-fed mice with inhibitors of ET formation or a TLR7/9 antagonist improves metabolic disease. These findings reveal a pathogenic role for nucleic acid targeting as a driver of metabolic inflammation in IR.

Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome

“…Other factors that might induce IFN-I responses in the liver include dietary fats, though our in vitro data for two dominant IRFs did not reach significance after addition of palmitate. Hepatocytes or IFN-I-producing intrahepatic immune cells, including plasmacytoid dendritic cells (pDCs), may be sources of IFN-I production which contribute to hepatic inflammation in obesity (48). …”

Evidence of an anti-inflammatory toll-like receptor 9 (TLR 9) pathway in adipocytes

“…Recent studies have hinted at an important role of TLR9 signaling in obesity, glucose intolerance and insulin resistance. In this context, TLR9 signaling in the visceral adipose tissue depot in particular seems to play a key role (Hong et al 2015, Ghosh et al 2016, Nishimoto et al 2016, Revelo et al 2016. However, the extent in which individual cell types within the complex adipose tissue microenvironment contribute to the observed effects remains elusive (Apostolopoulos et al 2016).…”

“…TLR9 has recently been postulated to play a role in obesity and insulin resistance (Hong et al 2015, Ghosh et al 2016, Nishimoto et al 2016. Insulin resistance has been associated to inflammatory changes in particular within the visceral adipose tissue compartment (Hardy et al 2012, Ghosh et al 2016, Revelo et al 2016. Thus, we asked if different fat depots exhibit distinct TLR9 expression profiles in vivo.…”

“…Recently, it has been shown that cell-free DNA (cfDNA) derived from apoptotic adipocytes and so-called extracellular traps (ETs) derived from macrophages and neutrophil granulocytes are increased in serum in murine obesity models as well as in human obese patients (Nishimoto et al 2016, Revelo et al 2016. cfDNA and ETs induce a TLR9-dependent pro-inflammatory transformation of visceral adipose tissue depots, which is mediated via adipose tissue-resident macrophages and liver-resident plasmacytoid dendritic cells (Ghosh et al 2016, Revelo et al 2016. TLR9-dependent production of interleukin-1β (IL-1β) by Kupffer cells induces hepatic steatosis, inflammation and fibrosis in mice fed a cholinedeficient amino acid-defined (CDAA) diet, a murine model of non-alcoholic steatohepatitis (NASH).…”

Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice

“…Consecutive injection of a toll-like receptor (TLR)-4 ligand, lipopolysaccharide (LPS), or viral infection can induce hyperglycemia and insulin resistance Sestan et al, 2018). Blocking TLR-7 and TLR-9 signaling improves obesity-related insulin resistance (Revelo et al, 2016). Thus, systemic psoriatic inflammation itself may play a key role in glucose metabolism.…”