title: The activation of hepatic and muscle polyamine catabolism improves glucose homeostasis.
abstract: The mitochondrial biogenesis and energy expenditure regulator, PGC-1α, has been previously reported to be induced in the white adipose tissue (WAT) and liver of mice overexpressing spermidine/spermine N (1)-acetyltransferase (SSAT). The activation of PGC-1α in these mouse lines leads to increased number of mitochondria, improved glucose homeostasis, reduced WAT mass and elevated basal metabolic rate. The constant activation of polyamine catabolism produces a futile cycle that greatly reduces the ATP pools and induces 5'-AMP-activated protein kinase (AMPK), which in turn activates PGC-1α in WAT. In this study, we have investigated the effects of activated polyamine catabolism on the glucose and energy metabolisms when targeted to specific tissues. For that we used a mouse line overexpressing SSAT under the endogenous SSAT promoter, an inducible SSAT overexpressing mouse model using the metallothionein I promoter (MT-SSAT), and a mouse model with WAT-specific SSAT overexpression (aP2-SSAT). The results demonstrated that WAT-specific SSAT overexpression was sufficient to increase the number of mitochondria, reduce WAT mass and protect the mice from high-fat diet-induced obesity. However, the improvement in the glucose homeostasis is achieved only when polyamine catabolism is enhanced at the same time in the liver and skeletal muscle. Our results suggest that the tissue-specific targeting of activated polyamine catabolism may reveal new possibilities for the development of drugs boosting mitochondrial metabolism and eventually for treatment of obesity and type 2 diabetes.
authors.affiliation: Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, P.O. Box 1627, 70211, Kuopio, Finland. taina.e.koponen@uef.fi
authors.forename: Taina
authors.initials: T
authors.lastname: Koponen
authors.forename: Marc
authors.initials: M
authors.lastname: Cerrada-Gimenez
authors.forename: Eija
authors.initials: E
authors.lastname: Pirinen
authors.forename: Esa
authors.initials: E
authors.lastname: Hohtola
authors.forename: Jussi
authors.initials: J
authors.lastname: Paananen
authors.forename: Susanna
authors.initials: S
authors.lastname: Vuohelainen
authors.forename: Maija
authors.initials: M
authors.lastname: Tusa
authors.forename: Sini
authors.initials: S
authors.lastname: Pirnes-Karhu
authors.forename: Sami
authors.initials: S
authors.lastname: Heikkinen
authors.forename: Antti
authors.initials: A
authors.lastname: Virkamäki
authors.forename: Anne
authors.initials: A
authors.lastname: Uimari
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015317:Biogenic Polyamines / Q000378:metabolism*; D015153:Blotting, Western; D001823:Body Composition; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D015317:Biogenic Polyamines; D017931:DNA Primers; D004272:DNA, Mitochondrial; D005947:Glucose; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators; D014157:Transcription Factors; D000099228:Diamine N-Acetyltransferase; C485290:Ppargc1a protein, mouse