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.
Pirinen
Eija
E
Department of Medicine, University of Kuopio, P.O. Box 1777, FI-70211 Kuopio, Finland.
Kuulasmaa
Teemu
T
Pietilä
Marko
M
Heikkinen
Sami
S
Tusa
Maija
M
Itkonen
Paula
P
Boman
Susanna
S
Skommer
Joanna
J
Virkamäki
Antti
A
Hohtola
Esa
E
Kettunen
Mikko
M
Fatrai
Szabolcs
S
Kansanen
Emilia
E
Koota
Suvi
S
Niiranen
Kirsi
K
Parkkinen
Jyrki
J
Levonen
Anna-Liisa
AL
Ylä-Herttuala
Seppo
S
Hiltunen
J Kalervo
JK
Alhonen
Leena
L
Smith
Ulf
U
Jänne
Juhani
J
Laakso
Markku
M
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
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