FIG. 9.

Proposed molecular mechanism leading to the phenotype of SSAT mice. Based on the data presented, it is hypothesized that the accelerated polyamine flux caused by enhanced polyamine catabolism in WAT leads to the high ATP consumption and the high AMP/ATP ratio which stimulates AMPK. This in turn induces the expression of PGC-1α, resulting in increased mitochondrial biogenesis, fatty acid oxidation, uncoupling, and insulin sensitivity. The enhanced polyamine catabolism also depletes the SSAT cofactor acetyl-CoA pool and therefore may cause impaired generation of malonyl-CoA by acetyl-CoA carboxylases (ACCs), leading to reduced fatty acid synthesis and increased fatty acid oxidation. DFMO is an inhibitor of ODC, and it reduces the biosynthesis of putrescine and therefore the rate of the polyamine cycle. PAO, polyamine oxidase; Spd, spermidine; Spm, spermine; Met, methionine; AdoMet, S-adenosylmethionine; AdoMetDC, S-adenosylmethionine decarboxylase; dcAdoMet, decarboxylated S-adenosylmethionine.