title: 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.affiliation: Department of Medicine, University of Kuopio, P.O. Box 1777, FI-70211 Kuopio, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Pirinen
authors.forename: Teemu
authors.initials: T
authors.lastname: Kuulasmaa
authors.forename: Marko
authors.initials: M
authors.lastname: Pietilä
authors.forename: Sami
authors.initials: S
authors.lastname: Heikkinen
authors.forename: Maija
authors.initials: M
authors.lastname: Tusa
authors.forename: Paula
authors.initials: P
authors.lastname: Itkonen
authors.forename: Susanna
authors.initials: S
authors.lastname: Boman
authors.forename: Joanna
authors.initials: J
authors.lastname: Skommer
authors.forename: Antti
authors.initials: A
authors.lastname: Virkamäki
authors.forename: Esa
authors.initials: E
authors.lastname: Hohtola
authors.forename: Mikko
authors.initials: M
authors.lastname: Kettunen
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Fatrai
authors.forename: Emilia
authors.initials: E
authors.lastname: Kansanen
authors.forename: Suvi
authors.initials: S
authors.lastname: Koota
authors.forename: Kirsi
authors.initials: K
authors.lastname: Niiranen
authors.forename: Jyrki
authors.initials: J
authors.lastname: Parkkinen
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.forename: Juhani
authors.initials: J
authors.lastname: Jänne
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
mesh_terms: D055372:AMP-Activated Protein Kinases; D000123:Acetyltransferases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005508:Food Deprivation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance; D006706:Homeostasis / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D011073:Polyamines / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099228:Diamine N-Acetyltransferase
chemical_list: D055372:AMP-Activated Protein Kinases; D000123:Acetyltransferases; D000255:Adenosine Triphosphate; D005947:Glucose; D006861:Hydrogen Peroxide; D007527:Isoenzymes; D009097:Multienzyme Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011073:Polyamines; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099228:Diamine N-Acetyltransferase; C485290:Ppargc1a protein, mouse