Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism

• Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is an attractive candidate gene for type 2 diabetes, as genes of the oxidative phosphorylation (OXPHOS) pathway are coordinatively downregulated by reduced expression of PGC-1 alpha in skeletal muscle and adipose tissue of patients with type 2 diabetes. Here we demonstrate that transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) had reduced white adipose tissue (WAT) mass, high basal metabolic rate, improved glucose tolerance, high insulin sensitivity, and enhanced expression of the OXPHOS genes, coordinated by increased levels of PGC-1 alpha and 5'-AMP-activated protein kinase (AMPK) in WAT. As accelerated polyamine flux caused by SSAT overexpression depleted the ATP pool in adipocytes of SSAT mice and N(1),N(11)-diethylnorspermine-treated wild-type fetal fibroblasts, we propose that low ATP levels lead to the induction of AMPK, which in turn activates PGC-1 alpha in WAT of SSAT mice. Our hypothesis is supported by the finding that the phenotype of SSAT mice was reversed when the accelerated polyamine flux was reduced by the inhibition of polyamine biosynthesis in WAT. The involvement of polyamine catabolism in the regulation of energy and glucose metabolism may offer a novel target for drug development for obesity and type 2 diabetes.

Nyckelord

Acetyltransferases/metabolism

Adenosine Triphosphate/metabolism

Adipocytes/drug effects/metabolism

Adipose Tissue

development

Animals

Body Composition/drug effects

*Energy Metabolism/drug effects

Feeding Behavior/drug effects

Fibroblasts/drug effects/metabolism

Food Deprivation

Gene Expression Regulation

Enzymologic/drug effects

Glucose/*metabolism

Glucose Intolerance

*Homeostasis/drug effects

Hydrogen Peroxide/pharmacology

Isoenzymes/genetics/metabolism

Macrophages/cytology/drug effects/metabolism

Mice

Mitochondria/drug effects/metabolism

Multienzyme Complexes/genetics/metabolism

Organ Size/drug effects

Oxidative Phosphorylation/drug effects

Phosphorylation/drug effects

Polyamines/*metabolism

Protein-Serine-Threonine Kinases/genetics/metabolism

Trans-Activators/genetics/metabolism

p38 Mitogen-Activated Protein Kinases/metabolism

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