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Molecular and Cellular Biology, July 2007, p. 4953-4967, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02034-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Enhanced Polyamine Catabolism Alters Homeostatic Control of White Adipose Tissue Mass, Energy Expenditure, and Glucose Metabolism

Eija Pirinen,^1,2 Teemu Kuulasmaa,¹ Marko Pietilä,^2, Sami Heikkinen,^1,2, Maija Tusa,^1,2 Paula Itkonen,¹ Susanna Boman,² Joanna Skommer,¹ Antti Virkamäki,³ Esa Hohtola,⁴ Mikko Kettunen,⁵ Szabolcs Fatrai,¹ Emilia Kansanen,² Suvi Koota,² Kirsi Niiranen,² Jyrki Parkkinen,⁶ Anna-Liisa Levonen,² Seppo Ylä-Herttuala,² J. Kalervo Hiltunen,⁷ Leena Alhonen,² Ulf Smith,⁸ Juhani Jänne,² and Markku Laakso^1*

Department of Medicine, University of Kuopio, FI-70211 Kuopio, Finland,¹ A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FI-70211 Kuopio, Finland,² Minerva Foundation Institute for Medical Research, University of Helsinki, FI-00290 Helsinki, Finland,³ Department of Biology, University of Oulu, FI-90014 Oulu, Finland,⁴ National Bio-NMR Facility, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FI-70211 Kuopio, Finland,⁵ Department of Pathology, University Hospital of Tampere, FI-33521 Tampere, Finland,⁶ Biocenter Oulu and Department of Biochemistry, University of Oulu, FI-90014 Oulu, Finland,⁷ The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, SE-41345 Göteborg, Sweden⁸

Received 31 October 2006/ Returned for modification 9 February 2007/ Accepted 25 April 2007

Peroxisome proliferator-activated receptor coactivator 1 (PGC-1) 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 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 N¹-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 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 N¹,N¹¹-diethylnorspermine-treated wild-type fetal fibroblasts, we propose that low ATP levels lead to the induction of AMPK, which in turn activates PGC-1 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.

Published ahead of print on 7 May 2007.

These authors contributed equally.

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