title: Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue.
abstract: Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing β1-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, Bonn D-53105, Germany.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Hoffmann
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, Bonn D-53105, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Etzrodt
authors.affiliation: Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Institute of Cardiovascular Research and Sports Medicine, Cologne D-50735, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Willkomm
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, Bonn D-53105, Germany.|Research Training Group 1873, University of Bonn, Bonn D-53127, Germany.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Sanyal
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Scheja
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany.
authors.forename: Alexander W C
authors.initials: AWC
authors.lastname: Fischer
authors.affiliation: Bayer Pharma AG, Wuppertal D-42113, Germany.|Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle an der Saale D-06120, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.affiliation: Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Institute of Cardiovascular Research and Sports Medicine, Cologne D-50735, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Institute of Physiology, Martin Luther University Würzburg, Würzburg D-97070, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Friebe
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, Bonn D-53105, Germany.|Research Training Group 1873, University of Bonn, Bonn D-53127, Germany.|PharmaCenter, University of Bonn, Bonn D-53119, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D002001:Adipose Tissue, Brown / Q000187:drug effects*; D052436:Adipose Tissue, White / Q000187:drug effects*; D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009765:Obesity / Q000188:drug therapy* / Q000517:prevention & control; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D022722:Thermogenesis; D015431:Weight Loss
chemical_list: C450679:BAY 41-8543; D009025:Morpholines; D011743:Pyrimidines; D006162:Guanylate Cyclase