Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1.
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.
Department of Biochemistry and Biomedical Sciences, and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Wendy
W
Chi
Department of Biochemistry and Biomedical Sciences, and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Dyda
D
Dao
Department of Biochemistry and Biomedical Sciences, and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Trevor C
TC
Lau
Department of Biochemistry and Biomedical Sciences, and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Brandyn D
BD
Henriksbo
Department of Biochemistry and Biomedical Sciences, and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Joseph F
JF
Cavallari
Department of Biochemistry and Biomedical Sciences, and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Kevin P
KP
Foley
Department of Biochemistry and Biomedical Sciences, and Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Jonathan D
JD
Schertzer
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006066:Gonads / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000172:deficiency / Q000235:genetics*; D010457:Peptidoglycan / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D046509:Tissue Culture Techniques
D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D010457:Peptidoglycan; D047428:Protein Kinase Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases