Gastroenterology

Gastroenterology

Volume 126, Issue 2, February 2004, Pages 499-510
Gastroenterology

Basic-alimentary tract
Leptin reduces the development of the initial precancerous lesions induced by azoxymethane in the rat colonic mucosa

https://doi.org/10.1053/j.gastro.2003.11.004Get rights and content

Abstract

Background & Aims: Recent studies suggest that leptin, a hormone involved in food intake regulation, released into the circulation and gastrointestinal juice, may be a growth factor for intestine and may be involved in carcinogenesis; however, data are contradictory. This study investigates in rat colonic mucosa (1) the effects of hyperleptinemia on epithelial cell proliferation and development of aberrant crypts, earliest preneoplastic lesions, and (2) whether luminal leptin affects cell proliferation. Methods: Leptin (1 mg/kg/d) or vehicle was administered systemically by miniosmotic pump in Fischer 344 rats either for 7 days (BrdU-labeling indices study) or 23 days (azoxymethane-induced colonic lesions study). The effects of injections or continuous infusion of leptin into the colon were also studied. Results: In systemic leptin-treated rats, plasma leptin levels were 4- to 5-fold increased (P < 0.008 to P < 0.001); labeling indices were higher in proximal colon than in pair-fed control rats (P = 0.006) but unaffected in distal colon. Unexpectedly, in azoxymethane-treated rats, leptin significantly inhibited aberrant crypt foci formation in the middle and distal colon compared with controls (P = 0.006). Under these conditions, plasma insulin levels were reduced by 41%–58%, but gastrin levels were unchanged. In controls, luminal immunoreactive leptin reached the colon. A 3.6-fold increase in intraluminal leptin had no effect on epithelial cell proliferation. Conclusions: This study provides the first evidence that leptin reduces the development of chemically induced precancerous lesions in colon, perhaps through decreased insulinemia, and thus does not support an important role for leptin in carcinogenesis promotion. Moreover, the study indicates that leptin is not a potent growth factor for normal intestine.

Section snippets

Animals

Male Fischer 344 rats were obtained from Iffa-Credo (Saint Germain sur l’Arbresle, France), housed in our animal quarters in individual cages, kept in a temperature-controlled room with a 12-hour light-dark period. They were given standard rat food pellets and water ad libitum. Animals were treated in accordance with European Community guidelines concerning the care and use of laboratory animals.

Study of colonic epithelial cell proliferation

Systemic administration of leptin: Rats (mean weight 280–300 g) were anesthetized with pentobarbital

Systemic administration of leptin stimulates epithelial cell proliferation in the right but not in the left colon

During the experiment, body weight curves were similar in pair-fed leptin-treated and vehicle-treated control rats, and no significant loss in body weight was observed (−2.5% and −2%, respectively), whereas untreated control Fischer 344 rats fed ad libitum had a 5% gain in body weight (Figure 1A). However, intraperitoneal administration of leptin for a week reduced the food intake by a mean of 57% compared with these control rats fed ad libitum (Figure 1B). Note that this reduction in food

Discussion

The present study reports for the first time a significant inhibitory effect of leptin on the initial stages of carcinogenesis in the rat colon and provides new interesting data about the potential growth action of leptin on the gut, particularly on the colonic epithelial cell proliferation.

Leptin has been considered by some authors as a growth factor for small intestine20 and colonic epithelial cells.15 Actually, if there are consensual opinions about the ability of leptin to stimulate in

References (49)

  • J.M. Friedman et al.

    Leptin and the regulation of body weight in mammals

    Nature

    (1998)
  • M. Maffei et al.

    Leptin levels in human and rodentmeasurement of plasma leptin and ob RNA in obese and weight-reduced subjects

    Nat Med

    (1995)
  • A. Giacosa et al.

    Energy intake, overweight, physical exercise and colorectal cancer risk

    Eur J Cancer Prev

    (1999)
  • T.K. Murphy et al.

    Body mass index and colon cancer mortality in a large prospective study

    Am J Epidemiol

    (2000)
  • S. Kono et al.

    Obesity, weight gain and risk of colon adenomas in Japanese men

    Jpn J Cancer Res

    (1999)
  • A. Bado et al.

    The stomach is a source of leptin

    Nature

    (1998)
  • S. Cinti et al.

    Secretory granules of endocrine and chief cells of human stomach mucosa contain leptin

    Int J Obes Relat Metab Disord

    (2000)
  • H. Mix et al.

    Expression of leptin and leptin receptor isoforms in the human stomach

    Gut

    (2000)
  • I. Sobhani et al.

    Leptin secretion and leptin receptor in the human stomach

    Gut

    (2000)
  • M. Groschl et al.

    Identification of leptin in human saliva

    J Clin Endocrinol Metab

    (2001)
  • S. Attoub et al.

    Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, rho-, and rac-dependent signaling pathways

    FASEB J

    (2000)
  • J. Barrenetxe et al.

    Distribution of the long leptin receptor isoform in brush border, basolateral membrane, and cytoplasm of enterocytes

    Gut

    (2002)
  • Z. Liu et al.

    High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin

    Int J Oncol

    (2001)
  • A. Bouloumie et al.

    Leptin, the product of Ob gene, promotes angiogenesis

    Circ Res

    (1998)
  • Cited by (0)

    Supported by the Institut de la Santé et de la Recherche médicale (INSERM) and the La Ligue contre le Cancer, Comité de Paris (No. 75-02/RS-7 to T.L.), and the Assistance Publique des Hôpitaux de Paris (to T.A.).

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