Overexpression of gastric leptin precedes adipocyte leptin during high-fat diet and is linked to 5HT-containing enterochromaffin cells.
OBJECTIVE
In obesity, while hyperleptinemia highly correlates with excess fat mass, the status of gastric leptin remains unknown. Here, we investigated the expression of leptin in stomach biopsies of obese humans and analyzed the temporal changes of gastric leptin expression in response to diet-induced obesity and its impact on 5-hydroxytryptamine (5HT)-producing cells.


METHODS
Enterochromaffin (EC) cells and expression of leptin, PAX4 (critical factor for EC specification), tryptophane hydroxylase-1 (TPH1, the peripheral rate-limiting enzyme for 5HT) and 5HT were examined by immunofluorescence, quantitative real-time PCR, radioimmunoassay, respectively, in stomach and duodenum biopsies from 19 obese and 14 normo-weighed individuals, and in mucosa scrapings from C57Bl6/J diet-induced obese mice, leptin-deficient ob/ob mice and intestine-specific leptin receptor isoform B-deficient mice.


RESULTS
Gastric mucosa of obese subjects displays an increased expression of leptin (LEP mRNA by fivefold and protein by twofold, P<0.01), TPH1 ((1.75-2.73, 95% confidence interval (CI)) vs (0.38-0.67, 95% CI); P<0.01) and PAX4 ((1.33-2.11, 95%CI) vs (0.62-0.81, 95% CI); P<0.01) as compared with normo-weighed individuals. In diet-induced obese mice, the overexpressions of gastric leptin, antral Pax4, Tph1 and increased EC cell number occurred before the onset of obesity and hyperleptinemia (reflect of adipocyte leptin production). In addition, leptin deficiency was associated with reduced Pax4 mRNA, whereas oral leptin treatment enhanced both Tph1 and Pax4 mRNA. Finally, mice with an intestine-specific deletion of leptin signaling exhibit significant decrease in duodenal mucosa 5HT content.


CONCLUSIONS
These data demonstrate that gastric leptin is upregulated in obese individuals. RESULTS from high-fat diet mice showed that overexpression of gastric leptin that is linked to gut '5HT pathway' occurred before the onset of obesity and expansion of fat mass. This may be relevant in the pathophysiology of obesity.
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Pierre et Marie Curie, Paris, France [3] AP-HP Hôpital Pitié-Salpêtrière, Paris, France.
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J
Le Beyec
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
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AL
Pelletier
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Department of Digestive Surgery, AP-HP Hôpital Bichat, Paris, France.
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Arapis
Department of Pathology, AP-HP Hôpital Bichat, Paris, France.
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Hourseau
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
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F
Cluzeaud
Department of Pathology, AP-HP Hôpital Bichat, Paris, France.
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Descatoire
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
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R
Ducroc
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France [3] Department of Gastroenterology, AP-HP Hôpital Bobigny, Avicenne, France.
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Aparicio
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France [3] Department of Gastroenterology and Nutrition, AP-HP Hôpital Beaujon, Clichy, France.
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F
Joly
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Department of Pathology, AP-HP Hôpital Bichat, Paris, France.
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Couvelard
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Department of Digestive Surgery, AP-HP Hôpital Bichat, Paris, France.
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JP
Marmuse
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
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M
Le Gall
1] Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
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Bado
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004386:Duodenum / Q000378:metabolism* / Q000473:pathology; D004759:Enterochromaffin Cells / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D011863:Radioimmunoassay; D060888:Real-Time Polymerase Chain Reaction; D013270:Stomach / Q000473:pathology; D014365:Tryptophan Hydroxylase / Q000378:metabolism*; D015854:Up-Regulation
D018398:Homeodomain Proteins; D020738:Leptin; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; C497467:TPH1 protein, human; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase