Bacterial Peptidoglycan Stimulates Adipocyte Lipolysis via NOD1

Abstract

Obesity is associated with inflammation that can drive metabolic defects such as hyperlipidemia and insulin resistance. Specific metabolites can contribute to inflammation, but nutrient intake and obesity are also associated with altered bacterial load in metabolic tissues (i.e. metabolic endotoxemia). These bacterial cues can contribute to obesity-induced inflammation. The specific bacterial components and host receptors that underpin altered metabolic responses are emerging. We previously showed that Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) activation with bacterial peptidoglycan (PGN) caused insulin resistance in mice. We now show that PGN induces cell-autonomous lipolysis in adipocytes via NOD1. Specific bacterial PGN motifs stimulated lipolysis in white adipose tissue (WAT) explants from WT, but not NOD1−/− mice. NOD1-activating PGN stimulated mitogen activated protein kinases (MAPK),protein kinase A (PKA), and NF-κB in 3T3-L1 adipocytes. The NOD1-mediated lipolysis response was partially reduced by inhibition of ERK1/2 or PKA alone, but not c-Jun N-terminal kinase (JNK). NOD1-stimulated lipolysis was partially dependent on NF-κB and was completely suppressed by inhibiting ERK1/2 and PKA simultaneously or hormone sensitive lipase (HSL). Our results demonstrate that bacterial PGN stimulates lipolysis in adipocytes by engaging a stress kinase, PKA, NF-κB-dependent lipolytic program. Bacterial NOD1 activation is positioned as a component of metabolic endotoxemia that can contribute to hyperlipidemia, systemic inflammation and insulin resistance by acting directly on adipocytes.

High-intensity exercise training increases the diversity and metabolic capacity of the mouse distal gut microbiota during diet-induced obesity

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Immunometabolism of obesity and diabetes: microbiota link compartmentalized immunity in the gut to metabolic tissue inflammation

“…More work needs to be done to determine which bacterial components penetrate into the circulation and metabolic tissues during obesity. This is important because these bacterial factors can have direct effects on metabolic cells that are a source of metabolic inflammation in tissues that control blood glucose [58,59]. These studies provide clear and compelling evidence that alterations to the microbiome can have lasting metabolic effects on the host and have revealed some of the potential immune responses involved.…”

Targeting macrophage scavenger receptor 1 promotes insulin resistance in obese male mice

“…Innate and adaptive immune responses in the adipose tissue and the intestine have been shown to connect inflammation with insulin resistance (Winer and Winer 2012;McPhee and Schertzer 2015;Winer et al 2016). Many sources of this metabolic inflammation have been characterized, including microbial or dietary components (Cani et al 2007;Oliveira et al 2013;Chi et al 2014;Henriksbo et al 2014;Caesar et al 2015), endogenous metabolites (Mills et al 2016;Liu et al 2017), xenobiotics (Pestana et al 2017), and therapeutic drugs Henriksbo and Schertzer 2015). Pattern recognition receptors (PRR) can bridge potential triggers of inflammation to metabolic outcomes by acting as sensors of pathogen-associated molecular patterns (PAMPs) and/ or damage-associated molecular patterns (DAMPs).…”