Proinflammatory role of leptin in experimental colitis in rats - Benefit of cholecystokinin-B antagonist and beta 3-agonist

Leptin, a hormone primarily secreted from adipocytes, plays a key role in c ontrolling body weight homeostasis. In vitro studies indicate that it is al so implicated in immune responses. Hyperleptinaemia has been reported in ac ute inflammation, especially during the early stages of intestinal inflamma tion in rats. The present study investigated the possible role of leptin in the pathogenesis of trinitrobenzene sulfonic acid (TNBS)-induced colitis i n rats. Since no specific antagonist of leptin is available, a CCK-B antago nist (YM022) and a beta3 agonist (BRL37344) were used in this study to inhi bit leptin secretion. Colitis was induced by intracolonic instillation of T NBS in rats. Five TNBS-groups were subcutaneously implanted with micropumps containing : placebo, YM022, BRL37344, BRL37344 and exogenous leptin simul taneously, or leptin alone. At sacrifices, colitis severity was assessed by macroscopic and histological scoring systems and by determination of tissu e myeloperoxidase activity. The TNBS-induced hyperleptinaemia was significa ntly reduced by YM022 and BRL37344 (p<0.05). Inhibition of leptin secretion markedly reduced colonic inflammation, whatever the criteria considered (i .e. macroscopic, histological or biochemical). In contrast, administration of exogenous leptin completely abolished the beneficial effect of leptin-lo wering drugs on colitis severity. These results provide the first direct ev idence for an important deleterious role of leptin in the pathogenesis of e xperimental intestinal inflammation and suggest that a pro-inflammatory act ivity is attributable to leptin in vivo. Further studies are required to de termine if these results have clinical significance. (C) 2001 Elsevier Scie nce Inc. All rights reserved.