Leptin reduces the development of the initial precancerous lesions induced by azoxymethane in the rat colonic mucosa.
OBJECTIVE
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.
Aparicio
Thomas
T
INSERM U 410; IFR 02, Faculté de Médecine Xavier Bichat, Paris, France.
Guilmeau
Sandra
S
Goiot
Hélène
H
Tsocas
Annick
A
Laigneau
Jean-Pierre
JP
Bado
André
A
Sobhani
Iradj
I
Lehy
Thérèse
T
D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007260:Infusion Pumps; D007267:Injections; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D002273:Carcinogens; D020738:Leptin; D011994:Recombinant Proteins; D001397:Azoxymethane