title: Genetic ablation of cGMP-dependent protein kinase type I causes liver inflammation and fasting hyperglycemia.
abstract: OBJECTIVE
  The nitric oxide/cGMP/cGMP-dependent protein kinase type I (cGKI) signaling pathway regulates cell functions that play a pivotal role in the pathogenesis of type 2 diabetes. However, the impact of a dysfunction of this pathway for glucose metabolism in vivo is unknown.
  
  
  METHODS
  The expression of cGKI in tissues relevant to insulin action was analyzed by immunohistochemistry. The metabolic consequences of a genetic deletion of cGKI were studied in mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice).
  
  
  RESULTS
  In wild-type mice, cGKI protein was detected in hepatic stellate cells, but not in hepatocytes, skeletal muscle, fat cells, or pancreatic β-cells. Compared with control animals, cGKI-SM mice had higher energy expenditure in the light phase associated with lower body weight and fat mass and increased insulin sensitivity. Mutant mice also showed higher fasting glucose levels, whereas insulin levels and intraperitoneal glucose tolerance test results were similar to those in control animals. Interleukin (IL)-6 signaling was strongly activated in the liver of cGKI-SM mice as demonstrated by increased levels of IL-6, phospho-signal transducer and activator of transcription 3 (Tyr 705), suppressor of cytokine signaling-3, and serum amyloid A2. Insulin-stimulated tyrosine phosphorylation of the insulin receptor in the liver was impaired in cGKI-SM mice. The fraction of Mac-2-positive macrophages in the liver was significantly higher in cGKI-SM mice than in control mice. In contrast with cGKI-SM mice, conditional knockout mice lacking cGKI only in the nervous system were normal with respect to body weight, energy expenditure, fasting glucose, IL-6, and insulin action in the liver.
  
  
  CONCLUSIONS
  Genetic deletion of cGKI in non-neuronal cells results in a complex metabolic phenotype, including liver inflammation and fasting hyperglycemia. Loss of cGKI in hepatic stellate cells may affect liver metabolism via a paracrine mechanism that involves enhanced macrophage infiltration and IL-6 signaling.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
authors.forename: Stefan Z
authors.initials: SZ
authors.lastname: Lutz
authors.forename: Anita M
authors.initials: AM
authors.lastname: Hennige
authors.forename: Susanne
authors.initials: S
authors.lastname: Feil
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerling
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Kröber
authors.forename: Michaela
authors.initials: M
authors.lastname: Rath
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D004435:Eating / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism / Q000235:genetics; D005215:Fasting / Q000097:blood* / Q000378:metabolism; D006943:Hyperglycemia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D011972:Receptor, Insulin; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse