C(2)-ceramide influences the expression and insulin-mediated regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 adipocytes.

• Cyclic nucleotide phosphodiesterase (PDE) 3B plays an important role in the antilipolytic action of insulin and, thereby, the release of fatty acids from adipocytes. Increased concentrations of circulating fatty acids as a result of elevated or unrestrained lipolysis cause insulin resistance. The lipolytic action of tumor necrosis factor (TNF)-alpha is thought to be one of the mechanisms by which TNF-alpha induces insulin resistance. Ceramide is the suggested second messenger of TNF-alpha action, and in this study, we used 3T3-L1 adipocytes to investigate the effects of C(2)-ceramide (a short-chain ceramide analog) on the expression and regulation of PDE3B and lipolysis. Incubation of adipocytes with 100 micromol/l C(2)-ceramide (N-acetyl-sphingosine) resulted in a time-dependent decrease of PDE3B activity, accompanied by decreased PDE3B protein expression. C(2)-ceramide, in a time- and dose-dependent manner, stimulated lipolysis, an effect that was blocked by H-89, an inhibitor of protein kinase A. These ceramide effects were prevented by 20 micromol/l troglitazone, an antidiabetic drug. In addition to downregulation of PDE3B, the antilipolytic action of insulin was decreased by ceramide treatment. These results, together with data from other studies on PDE3B and lipolysis in diabetic humans and animals, suggest a novel pathway by which ceramide induces insulin resistance. Furthermore, PDE3B is demonstrated to be a target for troglitazone action in adipocytes.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors

Drug Interactions

Enzyme Inhibitors/pharmacology

Insulin/*pharmacology

Insulin Resistance

Isoquinolines/pharmacology

Tumor Necrosis Factor/pharmacology

Transcription Factors/genetics

Thiazoles/pharmacology

Non-U.S. Gov't

Support

Sphingosine/*analogs & derivatives/*pharmacology

Cytoplasmic and Nuclear/genetics

Receptors

Lipolysis/*drug effects

Mice

Chromans/pharmacology

Western

Blotting

Animal

3'

5'-Cyclic-Nucleotide Phosphodiesterase/analysis/*metabolism

3T3 Cells

Adipocytes/*metabolism

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)