Elsevier

Peptides

Volume 25, Issue 1, January 2004, Pages 95-104
Peptides

The anti-inflammatory effect of leptin on experimental colitis: involvement of endogenous glucocorticoids

https://doi.org/10.1016/j.peptides.2003.11.005Get rights and content

Abstract

The present study was designed to compare the effect of leptin on acute colonic inflammation with that of acute stress exposure, which acts via the hypothalamic-pituitary-adrenal (HPA) axis. Sprague–Dawley rats of both sexes were administered intrarectally with acetic acid. Either leptin (10 μg/kg; i.p.) or saline was injected immediately before and 6 h after the induction of colitis. A group of rats was exposed to water avoidance stress (WAS) for 30 min at the 6th h of colitis induction. RU-486 (2 mg/kg; i.p.), a glucocorticoid receptor antagonist, was injected intraperitoneally, at 12 and 1 h before the initial leptin injection, and at 1 h before the second leptin injection or exposure to WAS. Rats were decapitated at 24 h and the distal 8 cm of the colon were removed for macroscopic and microscopic scoring, determination of tissue wet weight index (WI) and tissue myeloperoxidase activity (MPO). Acetic acid-induced colitis significantly increased macroscopic and microscopic damage scores, WI and MPO, compared to control group. Exposure to acute WAS or treatment with leptin reduced the elevations in damage scores, WI and MPO induced by colitis, but no additive inhibitory effect was observed when WAS and leptin were applied together. RU-486 treatment reversed the inhibitory effects of leptin or WAS on colonic inflammation. Our results demonstrate that exogenous leptin mimics the effects of HPA axis activation on colitis-induced inflammatory process. The results also suggest that the anti-inflammatory effect of leptin involves a tissue neutrophil-dependent mechanism and is dependent on the release of glucocorticoids.

Introduction

Leptin, the protein product of the ob/ob gene [49], is an adipose tissue derived [17] circulating hormone, which regulates energy homeostasis and body weight by balancing energy intake and expenditure [9]. A number of non-adipocyte tissues have also been reported to produce leptin, including placenta, stomach and fetal tissues [2], [28], [45], [47]. Leptin receptor isoforms have been shown in a wide variety of human and rodent tissues [22], including colonic tissue [21]. This wide expression of leptin receptors implicates different regulatory roles for leptin, other than fat mass regulation. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion [37], is capable of initiating intestinal nutrient absorption [8]. Leptin was proposed as a growth factor in human colonic epithelial cell lines and human colonic tissue [21]. Moroever, leptin plays a regulatory role in immunity, inflammation, and hematopoiesis and its production is acutely increased during infection and inflammation, as a part of the host’s acute phase response [14].

Although the influence of psychological stress on the symptoms and clinical course of intestinal inflammatory processes has long been recognized, it has recently received the attention of the researchers [10]. There is evidence that the central nervous system may amplify or modulate aspects of intestinal inflammation through the stimulation of the hypothalamo-pituito-adrenal (HPA) axis [1], [29]. Over the past several years, it has become apparent that the release of endogenous glucocorticoid hormones by the activation of HPA axis, mediates many of the effects of stress on the immune system. On the other hand, hyporesponsiveness of the HPA axis to stress has been implicated in the development and perpetuation of inflammation [39], [41]. It is well known that during an infection, pro-inflammatory cytokines, secreted by the activated immune cells, stimulate the release of systemic glucocorticoids, which play a beneficial role in limiting inflammatory responses. In addition, there is evidence that the hyperleptinemia induced by cytokines is an integral part of the acute phase response and necessary for comprehensive immunocompetence [16].

Compelling evidence suggests that a regulatory loop between endogenous leptin and the HPA axis is operative, where ACTH inhibits leptin secretion by adipose tissue and in turn leptin increases expression and secretion of ACTH [31]. However, chronic exogenous administration of leptin depresses pituitary ACTH production, corticotropin-releasing factor mRNA expression and inhibits corticostereone response to stress [31], [32], [34]. Moreover, leptin infusion was shown to inhibit the production of glucocorticoids from adrenals in vitro [18].

Recent studies have shown that leptin exerts potent gastroprotective activity against ischemia-reperfusion- [6] or ethanol-induced [7] damage and accelerates ulcer healing [25]. In contrast, inhibition of leptin secretion was shown to markedly reduce the colitis severity in trinitrobenzene sulfonic acid-induced colitis [3]. That is, it is not clear yet whether leptin has a pro-inflammatory or an anti-inflammatory activity in the pathogenesis of intestinal inflammation. Nevertheless, it is likely that leptin contributes to the anorexia and body weight loss associated particularly with the acute stages of intestinal inflammation.

Therefore, the present study was designed to investigate the effect of exogenous leptin on acute colonic inflammation, in comparison with acute stress exposure, which is known to act via the HPA axis. Moreover, we aimed to identify the involvement of endogenous glucocorticoids in the modulatory role of leptin in acetic acid-induced colitis.

Section snippets

Animals

Sprague–Dawley rats (250–300 g) of both sexes were used. Animals were housed in an air-conditioned room with 12:12 h light/dark cycles, where the temperature (22±1 °C) and relative humidity (65–70%) were kept constant. Rats were allowed access to water and rat chow ad libitum. This study was approved by the Marmara University School of Medicine, Animal Care and Use Committee.

Induction of experimental colitis

Before the induction of colitis, rats were deprived of food, but not water, for 18 h. Colitis was induced by a modification

Results

Induction of colitis by acetic acid enema resulted in high macroscopic and microscopic scores, accompanied by an elevated tissue wet weight index and an increased MPO activity, which were significantly different than the control group (P<0.001) (Fig. 1, Fig. 2, Fig. 3, Fig. 4). Application of stress for 30 min at the 6th h of colitis induction reversed all of the damage parameters significantly (P<0.001). Similarly, leptin treatment (10 μg/kg) applied before and 6 h after acetic acid enema,

Discussion

The results of the present study demonstrate that exogenous leptin, as well as acute psychological stress, alleviate acetic acid-induced colonic inflammation, by a neutrophil-dependent mechanism. Similar to the anti-inflammatory effect of acute stress exposure, leptin-induced improvement in the colonic damage is also reversed by the inhibition of glucocorticoid activity, suggesting the involvement of endogenous glucocorticoids in the anti-inflammatory effect of leptin.

Originally thought to be a

Acknowledgements

This study was supported by the Marmara University Scientific Research Foundation.

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    Present address: Department of Physiology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.

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