Mice with targeted disruption of spermidine/spermine N1-acetyltransferase gene maintain nearly normal tissue polyamine homeostasis but show signs of insulin resistance upon aging.
The N(1)-acetylation of spermidine or spermine by spermidine/spermine N(1)-acetyltransferase (SSAT) is the ratecontrolling enzymatic step in the polyamine catabolism. We have now generated SSAT knockout (SSAT-KO) mice, which confirmed our earlier results with SSATdeficient embryonic stem (ES) cells showing only slightly affected polyamine homeostasis, mainly manifested as an elevated molar ratio of spermidine to spermine in most tissues indicating the indispensability of SSAT for the spermidine backconversion. Contrary to SSAT deficient ES cells, polyamine pools in SSAT-KO mice remained almost unchanged in response to N(1),N(11)-diethylnorspermine (DENSPM) treatment compared to a significant reduction of the polyamine pools in the wild-type animals and ES cells. Furthermore, SSATKO mice were more sensitive to the toxicity exerted by DENSPM in comparison with wild-type mice. The latter finding indicates that inducible SSAT plays an essential role in vivo in DENSPM treatmentevoked polyamine depletion, but a controversial role in toxicity of DENSPM. Surprisingly, liver polyamine pools were depleted similarly in wild-type and SSAT-KO mice in response to carbon tetrachloride treatment. Further characterization of SSAT knockout mice revealed insulin resistance at old age which supported the role of polyamine catabolism in glucose metabolism detected earlier with our SSAT overexpressing mice displaying enhanced basal metabolic rate, high insulin sensitivity and improved glucose tolerance. Therefore SSAT knockout mice might serve as a novel mouse model for type 2 diabetes.
Niiranen
Kirsi
K
A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
Keinänen
Tuomo A
TA
Pirinen
Eija
E
Heikkinen
Sami
S
Tusa
Maija
M
Fatrai
Szabolcs
S
Suppola
Suvikki
S
Pietilä
Marko
M
Uimari
Anne
A
Laakso
Markku
M
Alhonen
Leena
L
Jänne
Juhani
J
D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000375:Aging; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005947:Glucose; D006706:Homeostasis; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011073:Polyamines / Q000378:metabolism*; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D002251:Carbon Tetrachloride; D005947:Glucose; D011073:Polyamines; D013095:Spermidine; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C059685:N(1),N(11)-diethylnorspermine