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

Abstract

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.

• Authors: Eija Pirinen, Teemu Kuulasmaa, Marko Pietilä, Sami Heikkinen, Maija Tusa, Paula Itkonen, Susanna Boman, Joanna Skommer, Antti Virkamäki, Esa Hohtola, Mikko Kettunen, Szabolcs Fatrai, Emilia Kansanen, Suvi Koota, Kirsi Niiranen, Jyrki Parkkinen, Anna-Liisa Levonen, Seppo Ylä-Herttuala, J Kalervo Hiltunen, Leena Alhonen, Ulf Smith, Juhani Jänne, Markku Laakso
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 27 Issue 13 Pg. 4953-67 (Jul 2007) ISSN: 0270-7306 [Print] United States
• PMID: 17485446 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• Multienzyme Complexes
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Polyamines
• Ppargc1a protein, mouse
• Trans-Activators
• Transcription Factors
• Adenosine Triphosphate
• Hydrogen Peroxide
• Acetyltransferases
• diamine N-acetyltransferase
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases
• Acetyltransferases (metabolism)
• Adenosine Triphosphate (metabolism)
• Adipocytes (drug effects, metabolism)
• Adipose Tissue, White (cytology, drug effects, enzymology, growth & 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)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Phosphorylation (drug effects)
• Polyamines (metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Trans-Activators (genetics, metabolism)
• Transcription Factors
• p38 Mitogen-Activated Protein Kinases (metabolism)