title: Interplay between Obesity-Induced Inflammation and cGMP Signaling in White Adipose Tissue.
abstract: Current worldwide figures suggest that obesity is pandemic. Understanding the underlying molecular mechanisms would help develop viable anti-obesity therapies. Here, we assess the influence of obesity-induced inflammation on white adipocyte cyclic guanosine monophosphate (cGMP) signaling, which is beneficial for adipocyte differentiation and thermogenesis. We find that murine gonadal and not inguinal fat is prone to obesity-induced inflammation. Correspondingly, the cGMP cascade is dysregulated in gonadal but not in inguinal fat of obese mice. Analysis of two independent human cohorts reveals a defective cGMP pathway only in visceral fat of obese subjects. Congruently, cGMP signaling is dysregulated in tumor necrosis factor α (TNF-α)-treated primary white adipocytes. TNF-α-mediated suppression of sGCβ1is mediated via NF-κB, whereas PKG is repressed by JNK signaling. Additionally, TNF-α-activated JNK signaling suppresses PPARγ and aP2. Taken together, the intensity of obesity-induced inflammation dictates the amplitude of cGMP signaling dysregulation in white adipocytes through distinct pathways.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany; Bonn International Graduate School of Drug Sciences, University of Bonn, 53127 Bonn, Germany.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Sanyal
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Naumann
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Linda Sarah
authors.initials: LS
authors.lastname: Hoffmann
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chabowska-Kita
authors.affiliation: Department of Medicine, Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Ehrlund
authors.affiliation: Genomics and Immunoregulation, Life and Medical Science Institute, University of Bonn, 53115 Bonn, Germany; Single Cell Genomics and Epigenomics Unit, German Center for Neurodegenerative Diseases, University of Bonn, 53115 Bonn, Germany; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlitzer
authors.affiliation: Department of Medicine, Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.affiliation: Department of Medicine, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany; Bonn International Graduate School of Drug Sciences, University of Bonn, 53127 Bonn, Germany. Electronic address: alexander.pfeifer@uni-bonn.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006066:Gonads / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D007264:Inguinal Canal / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: PKG; TNF-α; cGMP signaling; metaflammation; obesity; sGC