Genetic Ablation of cGMP-Dependent Protein Kinase Type I Causes Liver Inflammation and Fasting Hyperglycemia

  1. Robert Feil2
  1. 1Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
  2. 2Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
  3. 3Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
  4. 4Institute of Pathology, University of Tübingen, Tübingen, Germany
  5. 5Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
  1. Corresponding author: Hans-Ulrich Häring, hans-ulrich.haering{at}med.uni-tuebingen.de.
  1. H-.U.H. and R.F. contributed equally to this study.

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.

RESEARCH DESIGN AND 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.

Footnotes

  • Received July 7, 2010.
  • Accepted February 22, 2011.

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  1. Diabetes vol. 60 no. 5 1566-1576
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