title: Benzylamine antihyperglycemic effect is abolished by AOC3 gene invalidation in mice but not rescued by semicarbazide-sensitive amine oxidase expression under the control of aP2 promoter.
abstract: Semicarbazide-sensitive amine oxidase (SSAO) is a transmembrane enzyme that metabolizes primary amines from endogenous or dietary origin. SSAO is highly expressed in adipose, smooth muscle and endothelial cells. In each of these cell types, SSAO is implicated in different biological functions, such as glucose transport activation, extracellular matrix maturation and leucocyte extravasation, respectively. However, the physiological functions of SSAO and their involvement in pathogenesis remain uncompletely characterized. To better understand the role of adipose tissue SSAO, we investigated whether it was necessary and/or sufficient to produce the antihyperglycemic effect of the SSAO-substrate benzylamine, already reported in mice. Therefore, we crossed SSAO-deficient mice invalidated for AOC3 gene and transgenic mice expected to express human SSAO in an adipocyte-specific manner, under the control of aP2 promoter. The aP2-human AOC3 construct (aP2-hAOC3) was equally expressed in the adipose tissue of mice expressing or not the native murine form and almost absent in other tissues. However, the corresponding SSAO activity found in adipose tissue represented only 20 % that of control mice. As a consequence, the benzylamine antihyperglycemic effect observed during glucose tolerance test in control was abolished in AOC3-KO mice but not rescued in mice expressing aP2-hAOC3. The capacity of benzylamine or methylamine to activate glucose uptake in adipocytes exhibited parallel variations in the corresponding genotypes. Although the aP2-hAOC3 construct did not allow a total rescue of SSAO activity in adipose tissue, it could be assessed from our observations that adipocyte SSAO plays a pivotal role in the increased glucose tolerance promoted by pharmacological doses of benzylamine.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1048, I2MC, CHU Rangueil, 31432 Toulouse, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grès
authors.forename: Sandy
authors.initials: S
authors.lastname: Bour
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Christian
authors.initials: C
authors.lastname: Carpéné
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology; D006631:Amine Oxidase (Copper-Containing) / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001596:Benzylamines; D015815:Cell Adhesion Molecules; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; D008744:Methylamines; D011994:Recombinant Proteins; C030796:benzylamine; C027451:methylamine; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse; D008995:Monoamine Oxidase; D005947:Glucose