Oral Administration of Semicarbazide Limits Weight Gain together with Inhibition of Fat Deposition and of Primary Amine Oxidase Activity in Adipose Tissue

Josep Mercader,Zsuzsa Iffiú-Soltész,Christian Carpéné,Sandy Bour

doi:10.1155/2011/475786

Abstract

An enzyme hitherto named semicarbazide-sensitive amine oxidase (SSAO), involved in the oxidation of primary amines, is abundantly expressed in adipocytes. Although SSAO physiological functions remain unclear, several molecules inhibiting its activity have been described to limit fat accumulation in preadipocyte cultures or to reduce body weight gain in obese rodents. Here, we studied whether oral administration of semicarbazide, a prototypical SSAO inhibitor, limits fat deposition in mice. Prolonged treatment with semicarbazide at 0.125% in drinking water limited food and water consumption, hampered weight gain, and deeply impaired fat deposition. The adiposomatic index was reduced by 31%, while body mass was reduced by 15%. Such treatment completely inhibited SSAO, but did not alter MAO activity in white adipose tissue. Consequently, the insulin-like action of the SSAO substrate benzylamine on glucose transport was abolished in adipocytes from semicarbazide-drinking mice, while their insulin sensitivity was not altered. Although semicarbazide is currently considered as a food contaminant with deleterious effects, the SSAO inhibition it induces appears as a novel concept to modulate adipose tissue development, which is promising for antiobesity drug discovery.

Highlights

Pharmacological agents known to inhibit a membrane enzyme involved in the oxidation of various primary amines, and hitherto named semicarbazide-sensitive amine oxidase (SSAO, E.C. 1.4.3.6, pending novel classification E.C. 1.3.4.21) have been reported to limit body weight gain in diverse animal models
Semicarbazide is currently considered as a food contaminant with deleterious effects, the SSAO inhibition it induces appears as a novel concept to modulate adipose tissue development, which is promising for antiobesity drug discovery
As previously reported [28], the oxidation of the prototypic SSAO substrate benzylamine was inhibited by semicarbazide in all the homogenates

Summary

Introduction

Pharmacological agents known to inhibit a membrane enzyme involved in the oxidation of various primary amines, and hitherto named semicarbazide-sensitive amine oxidase (SSAO, E.C. 1.4.3.6, pending novel classification E.C. 1.3.4.21) have been reported to limit body weight gain in diverse animal models Most of these observations of such “slimming effect” with the tested agents were not expected since they were evidenced in studies initially focused on vascular pharmacology. By performing pharmacological research on arterial thickness alteration, Mercier and colleagues repeatedly administrated the reference inhibitor of SSAO, namely, semicarbazide, at 100 mg/kg bw/d to SpragueDawley [2], and Brown-Norway rats [3] In both models, the authors observed a dramatically reduced body weight gain in response to the SSAO inhibitor, which induced a decrease in the pressure resistance of arteries, as initially expected

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Conclusion