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Serotonin (5-HT) is a brain neurotransmitter instrumental for the antidepressant action of selective inhibitors of serotonin reuptake (SSRIs) while it also plays important roles in peripheral organs. Recently, the 5-HT oxidation products, 5-hydroxyindoleacetate and 5-methoxy-indoleacetate, have been shown to bind to peroxisome proliferator-activated receptor γ (PPARγ) and to enhance lipid accumulation in preadipocytes. Since we already reported that adipocytes exhibit elevated monoamine oxidase (MAO) and primary amine oxidase activities, we verified how adipocytes readily oxidize 5-HT, with the objective to determine whether such oxidation promotes PPARγ activation and lipid storage. To this aim, serotonin was tested on cultured 3T3 F442A preadipocytes and on human adipocytes. Results showed that 5-HT was oxidized by MAO in both models. Daily treatment of 3T3 F442A preadipocytes for 8 days with 100-500 μM 5-HT promoted triglyceride accumulation and emergence of adipogenesis markers. At 250 μM, 5-HT alone reproduced half of 50 nM insulin-induced adipogenesis, and exhibited an additive differentiating effect when combined with insulin. Moreover, the 5-HT-induced expression of PPARγ-responsive genes (PEPCK, aP2/FABP4) was blocked by GW 9662, a PPARγ-inhibitor, or by pargyline, a MAO-inhibitor. In human fat cells, 6-h exposure to 100 μM 5-HT increased PEPCK expression as did the PPARγ-agonist rosiglitazone. Since hydrogen peroxide, another amine oxidation product, did not reproduce such enhancement, we propose that serotonin can promote PPARγ activation in fat cells, via the indoleacetate produced during MAO-dependent oxidation. Such pathway could be involved in the adverse effects of several antidepressant SSRIs on body weight gain.

The major form of primary amine oxidase expressed in adipose tissue (AT) is encoded by AOC3 gene and is known as semicarbazide-sensitive amine oxidase, identical to vascular adhesion protein-1 (SSAO/VAP-1). Exogenous substrates of SSAO/VAP-1 (e.g. benzylamine) stimulate glucose transport in adipocytes and improve glucose tolerance when injected in diabetic rodents. Numerous reports on the circulating, soluble SSAO/VAP-1 have univocally evidenced an increase in diabetic conditions. However, only scarce studies have investigated whether obesity and/or diabetes is accompanied with variations of AOC3 expression in AT. Therefore, we compared the SSAO/VAP-1 content in different fat depots of db-/- mice (lacking leptin receptor and being hyperphagic, diabetic and obese) and db+/- littermates (normoglycemic and lean). AOC3 expression was increased in perigonadal and subcutaneous AT of db-/- mice, while the maximal velocity of benzylamine oxidation (V (max), expressed as pmoles of hydrogen peroxide produced/min/mg protein) increased only in the latter. Indeed, the relative abundance of primary amine oxidase was increased in subcutaneous AT of db-/- mice at all the levels: mRNA, protein and activity. While considering the overall capacity to oxidise amines contained in each depot, there was an increase in the hypertrophic fat pads of the obese db-/- mice, irrespective of their anatomical location, as a result of their dramatically larger mass than in lean db+/- control. Such higher amount of AT-bound primary amine oxidase warrants further studies to determine whether SSAO/VAP-1 inhibition or activation may be useful in treating metabolic diseases.

From the 16 to 18 July 2012, more than 80 scientists from 20 different countries participated to the international Amine Oxidase Conference held in Toulouse, France. This 15th edition of a biennial workshop organized since 1984 was an invaluable opportunity for discussing about novel insights relative to enzymes that were initially characterized to regulate neurotransmitter levels, at least those belonging to the family of biogenic amines. Thereafter, the monoamine oxidases (MAO) and other amine oxidases (AOs) have been recognized to belong to an even larger family, to work with different co-factors, to act on a wider variety of substrates, and to participate in an increasing number of physiological functions. The AOC2012 was held at the ‘‘Hotel de Region Midi Pyrenees’’ and a session was shared with the 4th Food and Health symposium, since, in an attempt to re-examine the amines, several presentations have introduced unexpected substrates, such as histone H3, that is deaminated on its lysine 4 by Lysyl oxidase-like 2 (LOXL2) or the intestinal histamine brought by ingestion of food items with questionable freshness or poor microbial quality, the removal of which can be performed by addition of engineered vegetal or bacterial diamine oxidase (DAO). Happily, there was no need to use such nutritional supplements with the ‘‘mediterranean food’’ provided by the restaurants selected for social programme. The wine and cheese tasting was surely a strong source of dietary amines, but was also an opportunity to learn that in French, AOC means ‘‘Appelation d’Origine Controlee’’ a label of food quality. However and unfortunately, this 15th edition missed several of the pioneers who have stimulated the interest in chemistry and pharmacology of amine oxidation and disseminated their importance to Life Sciences. Several of them are still active, studying various aspects of these fascinating AOs, trying to solve the complex nomenclature of the growing AO family, or deciphering unexpected properties of their ‘‘novel’’ substrates or inhibitors. So, let us pass in a few words all our admiration. Thus, thanks to Jean Shih, Keith Tipton, Moussa Youdim, Peter Yu, Frans Boomsma and several others who could not attend personally to this conference. More sadly, we also think in late Franca Buffoni who passed in September leaving us as legacy her achievements in copper-containing amine oxidase research. We will be influenced for a long while by her human qualities and by the future perspectives she has introduced for the functions and pharmacology of semicarbazidesensitive amine oxidase (SSAO), previously named BzAO, and presently called PrAO or VAP-1. But, accordingly to the adage, the show has gone on, and young investigators have presented in Toulouse recent findings in an attractive manner, several of them being awarded by poster prizes. ‘‘Less younger’’ researchers also focused interest on AOs, by describing to the international audience, several novel functions of amine metabolism in inflammation, neurotransmission, cognition, metabolism, differentiation, digestion, endocrinology, reproduction, and cancer. From the cumulative demonstration of the importance of VAP-1 inhibition for novel anti-inflammatory therapy to the bridge between inflammation and carcinogenesis that is supported by polyamine oxidation mediated by spermine oxidase (SMO), the connections between endogenous and dietary amines and their oxidases were multiplied during the conference. The importance of lysine-specific demethylases (LSDs) or unexpected consequences of the invalidation of MAOs orientates the current C. Carpene (&) A. Parini INSERM U1048, Institut de Medecine Moleculaire de Rangueil (I2MC), Universite Paul Sabatier, Toulouse, France e-mail: christian.carpene@inserm.fr