title: Increased cGMP promotes healthy expansion and browning of white adipose tissue.
abstract: With more than half a billion individuals affected worldwide, obesity has reached pandemic proportions. Development of "brown-like" or "brite" adipocytes within white adipose tissue (WAT) has potential antiobesity and insulin-sensitizing effects. We investigated the role of cyclic GMP (cGMP) signaling, focusing on cGMP-dependent protein kinase I (PKGI) in WAT. PKGI is expressed in murine WAT, primary adipocytes, and 3T3-L1. Treatment of adipocytes with cGMP resulted in increased adipogenesis, with a 54% increase in expression of peroxisome proliferator-activated receptor-γ. Lentiviral overexpression of PKGI further increased adipogenesis, whereas loss of PKGI significantly reduced adipogenic differentiation. In addition to adipogenic effects, PKGI had an antihypertrophic and anti-inflammatory effect via RhoA phosphorylation and reduction of proinflammatory adipokine expression. Moreover, PKGI induced a 4.3-fold increase in abundance of UCP-1 and the development of a brown-like thermogenic program in primary adipocytes. Notably, treatment of C57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 d caused 4.6-fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype ("browning") of WAT in vivo. Taken together, PKGI is a key regulator of cell size, adipokine secretion and browning of white fat depots and thus could be a valuable target in developing novel treatments for obesity.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany.
authors.forename: Michaela M
authors.initials: MM
authors.lastname: Mitschke
authors.forename: Linda S
authors.initials: LS
authors.lastname: Hoffmann
authors.forename: Thorsten
authors.initials: T
authors.lastname: Gnad
authors.forename: Daniela
authors.initials: D
authors.lastname: Scholz
authors.forename: Katja
authors.initials: K
authors.lastname: Kruithoff
authors.forename: Peter
authors.initials: P
authors.lastname: Mayer
authors.forename: Bodo
authors.initials: B
authors.lastname: Haas
authors.forename: Antonia
authors.initials: A
authors.lastname: Sassmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.forename: Ana
authors.initials: A
authors.lastname: Kilic
mesh_terms: D041721:3T3-L1 Cells / Q000166:cytology; D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D015398:Signal Transduction; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP