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Integrative Biology

Overexpression of gastric leptin precedes adipocyte leptin during high-fat diet and is linked to 5HT-containing enterochromaffin cells

International Journal of Obesity volume 38, pages 1357–1364 (2014)Cite this article

Subjects

Abstract

Objectives:

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.

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Acknowledgements

This research was supported by INSERM, AP-HP, Grants from French National Society of Gastroenterology (FARE- SFNGE) and ANR-ALIA R10004HH to AB.

Author Contributions

JLB, MLG and AB conceived and design the study. ALP, JPM, TA, KA and AC recruited subjects and provided biopsies. MH and FC performed experiments. JPM, RD, AC, FJ and MLG critically reviewed the manuscript. JLB and AB interpreted the data and wrote the paper.

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Authors and Affiliations

  1. Inserm UMR 1149, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France

    J Le Beyec, A-L Pelletier, K Arapis, F Cluzeaud, R Ducroc, T Aparicio, F Joly, A Couvelard, J-P Marmuse, M Le Gall & A Bado

  2. Université Pierre et Marie Curie, Paris, France

    J Le Beyec

  3. AP-HP Hôpital Pitié-Salpêtrière, Paris, France

    J Le Beyec

  4. Université Paris Diderot, Sorbonne Paris Cité, Paris, France

    A-L Pelletier, F Cluzeaud, R Ducroc, T Aparicio, F Joly, M Le Gall & A Bado

  5. Department of Digestive Surgery, AP-HP Hôpital Bichat, Paris, France

    K Arapis & J-P Marmuse

  6. Department of Pathology, AP-HP Hôpital Bichat, Paris, France

    M Hourseau, V Descatoire & A Couvelard

  7. Department of Gastroenterology, AP-HP Hôpital Bobigny, Avicenne, France

    T Aparicio

  8. Department of Gastroenterology and Nutrition, AP-HP Hôpital Beaujon, Clichy, France

    F Joly

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  1. J Le Beyec
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Le Beyec, J., Pelletier, AL., Arapis, K. et al. Overexpression of gastric leptin precedes adipocyte leptin during high-fat diet and is linked to 5HT-containing enterochromaffin cells. Int J Obes 38, 1357–1364 (2014). https://doi.org/10.1038/ijo.2014.14

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