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

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.

Figure 1

Body weight changes in mice treated or not with orally administered semicarbazide. Two groups of age- and weight-matched mice were constituted after weaning and before oral administration of semicarbazide (week 0), given at 125 mg/100 mL in drinking solution (semidrinking, open triangles), while control (black symbols) had free access to tap water. Mean ± SEM of 8 determinations. Different from corresponding control at *P < .05, **P < .01, ***P < .001.

Figure 2

Effect of chronic semicarbazide ingestion on adipose tissue mass in male mice. Mean ± SEM of 8 determinations of epididymal (EPIWAT), perirenal + retroperitoneal (PERWAT), or inguinal (SCWAT) fad pad weights. Different from corresponding control (black columns) at **P < .01, ***P < .001.

Figure 3

Effect of chronic semicarbazide ingestion on the cellularity of visceral adipose tissues. Adipocytes isolated from visceral adipose tissues were subjected to size analysis and counted according to the indicated distribution of cell diameter classes (a). Mean fat cell diameter was calculated (b) while DNA was extracted from pieces of visceral WAT and determined as described in Section 2 (c). Mean ± SEM of six mice per group. Different from control at *P < .05, **P < .01, ***P < .001.

Figure 4

Influence of 8-week oral administration of semicarbazide on benzylamine-induced glucose transport in mouse adipocytes. Visceral adipocytes were incubated with 0.1 mM benzylamine alone (bza) or combined with 0.1 mM vanadate (bza + van) for 2-DG uptake assay. Data are expressed as percentage of response to 100 nM insulin, which maximally stimulated basal uptake by 3.3 ± 0.4-fold in control (black columns) and by 4.8 ± 0.8-fold in semicarbazide-drinking mice (open columns). Mean ± SEM of 8 determinations. Different from control at **P < .01.

Figure 5

Influence of 8-week oral treatment with semicarbazide on the benzylamine (a) and tyramine (b) oxidation in subcutaneous WAT. Homogenates were preincubated for 15 minutes without (total oxidation, black columns), with 0.5 mM pargyline (in order to determine pargyline-sensitive component as MAO, open columns), or with 1 mM semicarbazide (to determine the semicarbazide-sensitive component as SSAO, shaded columns). Then, they were incubated for 30 minutes in the presence of 0.1 mM benzylamine (a) or 0.5 mM tyramine (b). Mean ± SEM of 6 determinations. Different from corresponding control at **P < .01, ***P < .001.