81 results on '"Guilmeau S"'
Search Results
2. Loss of intestinal ChREBP impairs absorption of dietary sugars and prevents glycemic excursion curves
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Charifi, W, primary, Fauveau, V, additional, Francese, L, additional, Grosfeld, A, additional, Le Gall, M, additional, Ourabah, S, additional, Ellero-Simatos, S, additional, Viel, T, additional, Cauzac, M, additional, Gueddouri, D, additional, Benhamed, F, additional, Tavitian, B, additional, Dentin, R, additional, Burnol, AF, additional, Postic, C, additional, and Guilmeau, S, additional
- Published
- 2021
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3. Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling
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Guilmeau, S, Flandez, M, Mariadason, J M, and Augenlicht, L H
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- 2010
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4. Decreased expression of Intestinal I- and L-FABP levels in rare human genetic lipid malabsorption syndromes
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Guilmeau, S., Niot, I., Laigneau, J. P., Devaud, H., Petit, V., Brousse, N., Bouvier, R., Ferkdadji, L., Besmond, C., Aggerbeck, L. P., Bado, A., and Samson-Bouma, M. E.
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- 2007
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5. KLF4 regulation in intestinal epithelial cell maturation
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Flandez, M., Guilmeau, S., Blache, P., and Augenlicht, L. H.
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- 2008
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6. Dysregulated CRTC1 activity is a novel component of PGE2 signaling that contributes to colon cancer growth
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Schumacher, Y, primary, Aparicio, T, additional, Ourabah, S, additional, Baraille, F, additional, Martin, A, additional, Wind, P, additional, Dentin, R, additional, Postic, C, additional, and Guilmeau, S, additional
- Published
- 2015
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7. P196 L’insuline contrôle l’activité de la voie Wnt/b-caténine dans le foie de souris via la SCD1 et la Porcupine
- Author
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Moldes, M., primary, Cabrae, R., additional, Dubuquoy, C., additional, Morzyglod, L., additional, Guilmeau, S., additional, Noblet, B., additional, Guillou, H., additional, Fève, B., additional, Postic, C., additional, and Burnol, A.F., additional
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- 2015
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8. P188 Implication du facteur de transcription ChREBP dans le maintien de l’homéostasie glucidique via la production intestinale de GLP-1
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Ourabah, S., primary, Bokhari, A., additional, Baraille, F., additional, Postic, C., additional, and Guilmeau, S., additional
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- 2015
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9. O33 L’invalidation spécifique du récepteur intestinal LEPR-B modifie l’activité des transporteurs entérocytaires et confère aux souris une moindre susceptibilité à l’obésité nutritionnelle
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Cavin, J.-B., primary, Tavernier, A., additional, Ducroc, R., additional, Denis, R.G., additional, Cluzeaud, F., additional, Guilmeau, S., additional, Barbot, L., additional, Kapel, N., additional, Buyse, M., additional, Le Beyec, J., additional, Joly, F., additional, Luquet, S., additional, Le Gall, M., additional, and Bado, A., additional
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- 2013
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10. P2161 Quelles sont les conséquences d’un régime riche en graisse sur les cellules entéroendocrines ?
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Aranias, T., primary, Grosfeld, A., additional, Cotillard, A., additional, Omar, A.A., additional, Tordjman, J., additional, Le Gall, M., additional, Benkouhi, A., additional, Garbin, K., additional, Lacorte, J.-M., additional, Brot-Laroche, E., additional, Clément, K., additional, Leturque, A., additional, Poitou, C., additional, Guilmeau, S., additional, and Serradas, P., additional
- Published
- 2013
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11. Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling
- Author
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Guilmeau, S, primary, Flandez, M, additional, Mariadason, J M, additional, and Augenlicht, L H, additional
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- 2009
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12. 303 ORAL Intestinal inactivation of canonical Notch signaling by removal of protein O-fucosyltransferase 1 triggers secretory cell fate differentiation
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Guilmeau, S., primary, Flandez, M., additional, Bancroft, L., additional, Stanley, P., additional, and Augenlicht, L.H., additional
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- 2007
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13. C27 - La leptine luminale inhibe l’absorption intestinale active de glucose
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Ducroc, R., primary, Guilmeau, S., additional, Akasbi, K., additional, Buyse, M., additional, Devaud, H., additional, and Bado, A., additional
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- 2006
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14. O33 L’invalidation spécifique du récepteur intestinal LEPR-B modifie l’activité des transporteurs entérocytaires et confère aux souris une moindre susceptibilité à l’obésité nutritionnelle
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Cavin, J.-B., Tavernier, A., Ducroc, R., Denis, R.G., Cluzeaud, F., Guilmeau, S., Barbot, L., Kapel, N., Buyse, M., Le Beyec, J., Joly, F., Luquet, S., Le Gall, M., and Bado, A.
- Published
- 2013
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15. Leptin reduces the development of the initial precancerous lesions induced by azoxymethane in the rat colonic mucosa
- Author
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Aparicio, T., Guilmeau, S., Goiot, H., Tsocas, A., Laigneau, J.P., Bado, A., Sobhani, I., and Lehy, T.
- 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.
- Published
- 2004
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16. High fat diet increases enteroendocrine L cell number in the jejunum of mice in conditions of insulin resistance
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Aranias, T., Gilet, J., Guilmeau, S., Alexandra Grosfeld, Le Gall, M., Brot-Laroche, E., Leturque, A., and Serradas, P.
17. Corrigendum to " O -GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis" [JHEP Reports 6 [2024] 100878].
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Ortega-Prieto P, Parlati L, Benhamed F, Regnier M, Cavalcante I, Montabord M, Onifarasoaniaina R, Favier M, Pavlovic N, Magusto J, Cauzac M, Pagesy P, Gautheron J, Desdouets C, Guilmeau S, Issad T, and Postic C
- Abstract
[This corrects the article DOI: 10.1016/j.jhepr.2023.100878.]., (© 2024 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)
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- 2024
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18. The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism.
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Benichou E, Seffou B, Topçu S, Renoult O, Lenoir V, Planchais J, Bonner C, Postic C, Prip-Buus C, Pecqueur C, Guilmeau S, Alves-Guerra MC, and Dentin R
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- Humans, Transcription Factors genetics, Transcription Factors metabolism, Proto-Oncogene Proteins c-akt metabolism, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction, Carcinogenesis, Cell Proliferation, Cell Line, Tumor, Carcinoma, Hepatocellular metabolism, Liver Neoplasms metabolism
- Abstract
Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment., (© 2024. The Author(s).)
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- 2024
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19. O -GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis.
- Author
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Ortega-Prieto P, Parlati L, Benhamed F, Regnier M, Cavalcante I, Montabord M, Onifarasoaniaina R, Favier M, Pavlovic N, Magusto J, Cauzac M, Pagesy P, Gautheron J, Desdouets C, Guilmeau S, Issad T, and Postic C
- Abstract
Background & Aims: O -GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). In the liver, O -GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease., Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGT
LKO ) were generated and challenged with different carbohydrate- and lipid-containing diets., Results: Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver., Conclusions: These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis., Impact and Implications: Our study shows that hepatocyte-specific deletion of O -GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O -GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet ( i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies., Competing Interests: The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (.)- Published
- 2023
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20. Insulin resistance per se drives early and reversible dysbiosis-mediated gut barrier impairment and bactericidal dysfunction.
- Author
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Gueddouri D, Caüzac M, Fauveau V, Benhamed F, Charifi W, Beaudoin L, Rouland M, Sicherre F, Lehuen A, Postic C, Boudry G, Burnol AF, and Guilmeau S
- Subjects
- Animals, Dysbiosis metabolism, Dysbiosis microbiology, Inflammation metabolism, Mice, Diabetes Mellitus, Experimental, Gastrointestinal Microbiome physiology, Insulin Resistance
- Abstract
Objective: A common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the mechanistic bases underlying these features upon the diabesity cascade remain partly understood., Methods: Here, we show in mice that, independently of obesity, the induction of acute and global insulin resistance and associated hyperglycemia, upon treatment with an insulin receptor (IR) antagonist (S961), elicits gut hyperpermeability without triggering systemic inflammatory response., Results: Of note, S961-treated diabetic mice display major defects of gut barrier epithelial functions, such as increased epithelial paracellular permeability and impaired cell-cell junction integrity. We also observed in these mice the early onset of a severe gut dysbiosis, as characterized by the bloom of pro-inflammatory Proteobacteria, and the later collapse of Paneth cells antimicrobial defense. Interestingly, S961 treatment discontinuation is sufficient to promptly restore both the gut microbial balance and the intestinal barrier integrity. Moreover, fecal transplant approaches further confirm that S961-mediated dybiosis contributes at least partly to the disruption of the gut selective epithelial permeability upon diabetic states., Conclusions: Together, our results highlight that insulin signaling is an indispensable gatekeeper of intestinal barrier integrity, acting as a safeguard against microbial imbalance and acute infections by enteropathogens., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2022
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21. Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia.
- Author
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Rouland M, Beaudoin L, Rouxel O, Bertrand L, Cagninacci L, Saffarian A, Pedron T, Gueddouri D, Guilmeau S, Burnol AF, Rachdi L, Tazi A, Mouriès J, Rescigno M, Vergnolle N, Sansonetti P, Christine Rogner U, and Lehuen A
- Subjects
- Animals, Cytokines metabolism, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 1 microbiology, Disease Models, Animal, Epithelial Cells metabolism, Epithelial Cells pathology, Hyperglycemia etiology, Inflammation etiology, Intestinal Mucosa metabolism, Mice, Bacteria isolation & purification, Diabetes Mellitus, Type 1 complications, Dysbiosis etiology, Gastrointestinal Microbiome, Intestinal Mucosa microbiology, Intestinal Mucosa pathology
- Abstract
Objective: Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia., Design: We used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset., Results: We show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence., Conclusion: Our results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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22. [AMPK activity is a gatekeeper of the intestinal epithelial barrier].
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Olivier S, Diounou H, Foretz M, Guilmeau S, Daniel N, Marette A, Rolli-Derkinderen M, and Viollet B
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- Epithelial Cells, Humans, Intestinal Mucosa, AMP-Activated Protein Kinases, Intestines
- Published
- 2022
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23. Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability but not glucose homeostasis.
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Olivier S, Pochard C, Diounou H, Castillo V, Divoux J, Alcantara J, Leclerc J, Guilmeau S, Huet C, Charifi W, Varin TV, Daniel N, Foretz M, Neunlist M, Salomon BL, Ghosh P, Marette A, Rolli-Derkinderen M, and Viollet B
- Subjects
- Animals, Bacteria classification, Bacteria genetics, Diabetes Mellitus, Type 2 metabolism, Diet, High-Fat adverse effects, Disease Models, Animal, Epithelial Cells metabolism, Feces microbiology, Gastrointestinal Microbiome, Intestinal Mucosa metabolism, Male, Metformin pharmacology, Mice, Mice, Knockout, Obesity metabolism, Permeability drug effects, RNA, Ribosomal, 16S, AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Colon metabolism, Glucose metabolism, Homeostasis
- Abstract
Objective: The intestinal epithelial barrier (IEB) restricts the passage of microbes and potentially harmful substances from the lumen through the paracellular space, and rupture of its integrity is associated with a variety of gastrointestinal disorders and extra-digestive diseases. Increased IEB permeability has been linked to disruption of metabolic homeostasis leading to obesity and type 2 diabetes. Interestingly, recent studies have uncovered compelling evidence that the AMP-activated protein kinase (AMPK) signaling pathway plays an important role in maintaining epithelial cell barrier function. However, our understanding of the function of intestinal AMPK in regulating IEB and glucose homeostasis remains sparse., Methods: We generated mice lacking the two α1 and α2 AMPK catalytic subunits specifically in intestinal epithelial cells (IEC AMPK KO) and determined the physiological consequences of intestinal-specific deletion of AMPK in response to high-fat diet (HFD)-induced obesity. We combined histological, functional, and integrative analyses to ascertain the effects of gut AMPK loss on intestinal permeability in vivo and ex vivo and on the development of obesity and metabolic dysfunction. We also determined the impact of intestinal AMPK deletion in an inducible mouse model (i-IEC AMPK KO) by measuring IEB function, glucose homeostasis, and the composition of gut microbiota via fecal 16S rRNA sequencing., Results: While there were no differences in in vivo intestinal permeability in WT and IEC AMPK KO mice, ex vivo transcellular and paracellular permeability measured in Ussing chambers was significantly increased in the distal colon of IEC AMPK KO mice. This was associated with a reduction in pSer425 GIV phosphorylation, a marker of leaky gut barrier. However, the expression of tight junction proteins in intestinal epithelial cells and pro-inflammatory cytokines in the lamina propria were not different between genotypes. Although the HFD-fed AMPK KO mice displayed suppression of the stress polarity signaling pathway and a concomitant increase in colon permeability, loss of intestinal AMPK did not exacerbate body weight gain or adiposity. Deletion of AMPK was also not sufficient to alter glucose homeostasis or the acute glucose-lowering action of metformin in control diet (CD)- or HFD-fed mice. CD-fed i-IEC AMPK KO mice also presented higher permeability in the distal colon under homeostatic conditions but, surprisingly, this was not detected upon HFD feeding. Alteration in epithelial barrier function in the i-IEC AMPK KO mice was associated with a shift in the gut microbiota composition with higher levels of Clostridiales and Desulfovibrionales., Conclusions: Altogether, our results revealed a significant role of intestinal AMPK in maintaining IEB integrity in the distal colon but not in regulating glucose homeostasis. Our data also highlight the complex interaction between gut microbiota and host AMPK., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2021
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24. Dual regulation of TxNIP by ChREBP and FoxO1 in liver.
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Noblet B, Benhamed F, O-Sullivan I, Zhang W, Filhoulaud G, Montagner A, Polizzi A, Marmier S, Burnol AF, Guilmeau S, Issad T, Guillou H, Bernard C, Unterman T, and Postic C
- Abstract
TxNIP (Thioredoxin-interacting protein) is considered as a potential drug target for type 2 diabetes. Although TxNIP expression is correlated with hyperglycemia and glucotoxicity in pancreatic β cells, its regulation in liver cells has been less investigated. In the current study, we aim at providing a better understanding of Txnip regulation in hepatocytes in response to physiological stimuli and in the context of hyperglycemia in db/db mice. We focused on regulatory pathways governed by ChREBP (Carbohydrate Responsive Element Binding Protein) and FoxO1 (Forkhead box protein O1), transcription factors that play central roles in mediating the effects of glucose and fasting on gene expression, respectively. Studies using genetically modified mice reveal that hepatic TxNIP is up-regulated by both ChREBP and FoxO1 in liver cells and that its expression strongly correlates with fasting, suggesting a major role for this protein in the physiological adaptation to nutrient restriction., Competing Interests: The authors declare no conflict of interest., (© 2021.)
- Published
- 2021
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25. Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine.
- Author
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Cabrae R, Dubuquoy C, Caüzac M, Morzyglod L, Guilmeau S, Noblet B, Fève B, Postic C, Burnol AF, and Moldes M
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- Acyltransferases metabolism, Animals, Fatty Acids, Monounsaturated pharmacology, Hepatocytes metabolism, Lipogenesis drug effects, Liver metabolism, Liver pathology, Male, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Stearoyl-CoA Desaturase genetics, Stearoyl-CoA Desaturase metabolism, Sterol Regulatory Element Binding Protein 1 metabolism, Wnt Signaling Pathway physiology, beta Catenin metabolism, Insulin metabolism, Wnt Signaling Pathway drug effects, beta Catenin drug effects
- Abstract
The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.
- Published
- 2020
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26. UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses.
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Aguilar E, Esteves P, Sancerni T, Lenoir V, Aparicio T, Bouillaud F, Dentin R, Prip-Buus C, Ricquier D, Pecqueur C, Guilmeau S, and Alves-Guerra MC
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- Aged, Aged, 80 and over, Animals, Carcinogenesis metabolism, Colon metabolism, Colon pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Glycolysis, Humans, Intestine, Small metabolism, Intestine, Small pathology, Male, Mice, Mice, Inbred C57BL, Middle Aged, Uncoupling Protein 2 genetics, Carcinogenesis genetics, Colorectal Neoplasms metabolism, Lipogenesis, NADP metabolism, Oxidative Stress, Uncoupling Protein 2 metabolism
- Abstract
Colorectal cancer (CRC) is associated with metabolic and redox perturbation. The mitochondrial transporter uncoupling protein 2 (UCP2) controls cell proliferation in vitro through the modulation of cellular metabolism, but the underlying mechanism in tumors in vivo remains unexplored. Using murine intestinal cancer models and CRC patient samples, we find higher UCP2 protein levels in tumors compared to their non-tumoral counterparts. We reveal the tumor-suppressive role of UCP2 as its deletion enhances colon and small intestinal tumorigenesis in AOM/DSS-treated and Apc
Min/+ mice, respectively, and correlates with poor survival in the latter model. Mechanistically, UCP2 loss increases levels of oxidized glutathione and proteins in tumors. UCP2 deficiency alters glycolytic pathways while promoting phospholipid synthesis, thereby limiting the availability of NADPH for buffering oxidative stress. We show that UCP2 loss renders colon cells more prone to malignant transformation through metabolic reprogramming and perturbation of redox homeostasis and could favor worse outcomes in CRC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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27. O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells.
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Filhoulaud G, Benhamed F, Pagesy P, Bonner C, Fardini Y, Ilias A, Movassat J, Burnol AF, Guilmeau S, Kerr-Conte J, Pattou F, Issad T, and Postic C
- Abstract
Thioredoxin interacting protein (TxNIP), which strongly responds to glucose, has emerged as a central mediator of glucotoxicity in pancreatic β cells. TxNIP is a scaffold protein interacting with target proteins to inhibit or stimulate their activity. Recent studies reported that high glucose stimulates the interaction of TxNIP with the inflammasome protein NLRP3 (NLR family, pyrin domain containing 3) to increase interleukin-1 β (IL1β) secretion by pancreatic β cells. To better understand the regulation of TxNIP by glucose in pancreatic β cells, we investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAcylation) in regulating TxNIP at the posttranslational level. O-GlcNAcylation of proteins is controlled by two enzymes: the O-GlcNAc transferase (OGT), which transfers a monosaccharide to serine/threonine residues on target proteins, and the O-GlcNAcase (OGA), which removes it. Our study shows that TxNIP is subjected to O-GlcNAcylation in response to high glucose concentrations in β cell lines. Modification of the O-GlcNAcylation pathway through manipulation of OGT or OGA expression or activity significantly modulates TxNIP O-GlcNAcylation in INS1 832/13 cells. Interestingly, expression and O-GlcNAcylation of TxNIP appeared to be increased in islets of diabetic rodents. At the mechanistic level, the induction of the O-GlcNAcylation pathway in human and rat islets promotes inflammasome activation as evidenced by enhanced cleaved IL1β. Overexpression of OGT in HEK293 or INS1 832/13 cells stimulates TxNIP and NLRP3 interaction, while reducing TxNIP O-GlcNAcylation through OGA overexpression destabilizes this interaction. Altogether, our study reveals that O-GlcNAcylation represents an important regulatory mechanism for TxNIP activity in β cells.
- Published
- 2019
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28. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.
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Jarry AC, Merah N, Cisse F, Cayetanot F, Fiamma MN, Willemetz A, Gueddouri D, Barka B, Valet P, Guilmeau S, Bado A, Le Beyec J, Bodineau L, and Le Gall M
- Subjects
- Animals, Body Weight drug effects, Eating drug effects, Gastrointestinal Microbiome drug effects, Glucose Tolerance Test methods, Male, Mice, Mice, Inbred C57BL, Blood Glucose drug effects, Gastric Emptying drug effects, Glucose metabolism, Neuropeptides pharmacology, Peptides pharmacology, Pylorus drug effects, Vagus Nerve drug effects
- Abstract
The gut-brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose-dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c-FOS-positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.-Jarry, A.-C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.-N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.
- Published
- 2019
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29. Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.
- Author
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Morigny P, Houssier M, Mairal A, Ghilain C, Mouisel E, Benhamed F, Masri B, Recazens E, Denechaud PD, Tavernier G, Caspar-Bauguil S, Virtue S, Sramkova V, Monbrun L, Mazars A, Zanoun M, Guilmeau S, Barquissau V, Beuzelin D, Bonnel S, Marques M, Monge-Roffarello B, Lefort C, Fielding B, Sulpice T, Astrup A, Payrastre B, Bertrand-Michel J, Meugnier E, Ligat L, Lopez F, Guillou H, Ling C, Holm C, Rabasa-Lhoret R, Saris WHM, Stich V, Arner P, Rydén M, Moro C, Viguerie N, Harms M, Hallén S, Vidal-Puig A, Vidal H, Postic C, and Langin D
- Subjects
- Adipose Tissue metabolism, Animals, Biomarkers, Fatty Acid Elongases genetics, Fatty Acid Elongases metabolism, Gene Expression, Glucose metabolism, Membrane Fluidity genetics, Mice, Mice, Transgenic, Protein Interaction Mapping, Protein Interaction Maps, Signal Transduction, Adipocytes metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Insulin metabolism, Insulin Resistance genetics, Sterol Esterase metabolism
- Abstract
Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.
- Published
- 2019
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30. MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells.
- Author
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Richards P, Rachdi L, Oshima M, Marchetti P, Bugliani M, Armanet M, Postic C, Guilmeau S, and Scharfmann R
- Subjects
- Active Transport, Cell Nucleus drug effects, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors antagonists & inhibitors, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Line, Cyclic AMP metabolism, Exenatide, Humans, Incretins pharmacology, Insulin Secretion, Insulin-Secreting Cells drug effects, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Peptides pharmacology, RNA Interference, Thioredoxins genetics, Thioredoxins metabolism, Tissue Culture Techniques, Venoms pharmacology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Gene Expression Regulation drug effects, Glucose metabolism, Insulin metabolism, Insulin-Secreting Cells metabolism, Second Messenger Systems drug effects
- Abstract
Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels., (© 2017 by the American Diabetes Association.)
- Published
- 2018
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31. A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response.
- Author
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Iroz A, Montagner A, Benhamed F, Levavasseur F, Polizzi A, Anthony E, Régnier M, Fouché E, Lukowicz C, Cauzac M, Tournier E, Do-Cruzeiro M, Daujat-Chavanieu M, Gerbal-Chalouin S, Fauveau V, Marmier S, Burnol AF, Guilmeau S, Lippi Y, Girard J, Wahli W, Dentin R, Guillou H, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cells, Cultured, Female, Fibroblast Growth Factors genetics, Hepatocytes metabolism, Male, Mice, Mice, Inbred C57BL, Nuclear Proteins genetics, PPAR alpha genetics, Response Elements, Transcription Factors genetics, Fibroblast Growth Factors metabolism, Glucose metabolism, Nuclear Proteins metabolism, PPAR alpha metabolism, Transcription Factors metabolism
- Abstract
While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp
-/- mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp-/- mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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32. Sweet Sixteenth for ChREBP: Established Roles and Future Goals.
- Author
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Abdul-Wahed A, Guilmeau S, and Postic C
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Humans, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Glucose metabolism, Lipogenesis physiology, Liver metabolism
- Abstract
With the identification of ChREBP in 2001, our interest in understanding the molecular control of carbohydrate sensing has surged. While ChREBP was initially studied as a master regulator of lipogenesis in liver and fat tissue, it is now clear that ChREBP functions as a central metabolic coordinator in a variety of cell types in response to environmental and hormonal signals, with wide implications in health and disease. Celebrating its sweet sixteenth birthday, we review here the current knowledge about the function and regulation of ChREBP throughout usual and less explored tissues, to recapitulate ChREBP's role as a whole-body glucose sensor., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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33. MondoA/ChREBP: The usual suspects of transcriptional glucose sensing; Implication in pathophysiology.
- Author
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Richards P, Ourabah S, Montagne J, Burnol AF, Postic C, and Guilmeau S
- Subjects
- Animals, Energy Metabolism physiology, Glucose metabolism, Glycolysis, Humans, Lipogenesis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Transcription Factors physiology
- Abstract
Identification of the Mondo glucose-responsive transcription factors family, including the MondoA and MondoB/ChREBP paralogs, has shed light on the mechanism whereby glucose affects gene transcription. They have clearly emerged, in recent years, as key mediators of glucose sensing by multiple cell types. MondoA and ChREBP have overlapping yet distinct expression profiles, which underlie their downstream targets and separate roles in regulating genes involved in glucose metabolism. MondoA can restrict glucose uptake and influences energy utilization in skeletal muscle, while ChREBP signals energy storage through de novo lipogenesis in liver and white adipose tissue. Because Mondo proteins mediate metabolic adaptations to changing glucose levels, a better understanding of cellular glucose sensing through Mondo proteins will likely uncover new therapeutic opportunities in the context of the imbalanced glucose homeostasis that accompanies metabolic diseases such as type 2 diabetes and cancer. Here, we provide an overview of structural homologies, transcriptional partners as well as the nutrient and hormonal mechanisms underlying Mondo proteins regulation. We next summarize their relative contribution to energy metabolism changes in physiological states and the evolutionary conservation of these pathways. Finally, we discuss their possible targeting in human pathologies., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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34. Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma.
- Author
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Morzyglod L, Caüzac M, Popineau L, Denechaud PD, Fajas L, Ragazzon B, Fauveau V, Planchais J, Vasseur-Cognet M, Fartoux L, Scatton O, Rosmorduc O, Guilmeau S, Postic C, Desdouets C, Desbois-Mouthon C, and Burnol AF
- Subjects
- Animals, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular metabolism, Cell Line, Tumor, Cell Proliferation genetics, Cells, Cultured, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 metabolism, Disease Models, Animal, Down-Regulation, Hepatocytes cytology, Hepatocytes metabolism, Humans, Liver Neoplasms epidemiology, Liver Neoplasms metabolism, Male, Mice, Mice, Inbred C57BL, Random Allocation, Sensitivity and Specificity, Adaptor Proteins, Signal Transducing genetics, Carcinoma, Hepatocellular physiopathology, Diabetes Mellitus, Type 2 physiopathology, Liver Neoplasms physiopathology, Receptor, Insulin metabolism
- Abstract
Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation, we specifically inhibited its liver expression using a short hairpin RNA strategy in mice. Enhanced insulin signaling upon Grb14 inhibition was accompanied by a transient induction of S-phase entrance by quiescent hepatocytes, indicating that Grb14 is a potent repressor of cell division. The proliferation of Grb14-deficient hepatocytes was cell-autonomous as it was also observed in primary cell cultures. Combined Grb14 down-regulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14 inhibition-mediated hepatocyte division involved insulin receptor activation and was mediated by the mechanistic target of rapamycin complex 1-S6K pathway and the transcription factor E2F1. In order to determine a potential dysregulation in GRB14 gene expression in human pathophysiology, a collection of 85 human HCCs was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, with 60% of the tumors exhibiting a reduced Grb14 mRNA level., Conclusion: Our study establishes Grb14 as a physiological repressor of insulin mitogenic action in the liver and further supports that dysregulation of insulin signaling is associated with HCC. (Hepatology 2017;65:1352-1368)., (© 2016 by the American Association for the Study of Liver Diseases.)
- Published
- 2017
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35. Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance.
- Author
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Popineau L, Morzyglod L, Carré N, Caüzac M, Bossard P, Prip-Buus C, Lenoir V, Ragazzon B, Fauveau V, Robert L, Guilmeau S, Postic C, Komatsu M, Canonne-Hergaux F, Guillou H, and Burnol AF
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Gene Expression Regulation, Gene Knockdown Techniques, Liver cytology, Liver X Receptors metabolism, Mice, NF-E2-Related Factor 2 metabolism, Proteins metabolism, Receptor, Insulin metabolism, Insulin Resistance, Lipogenesis, Liver metabolism, Proteins genetics, Signal Transduction
- Abstract
A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
- Full Text
- View/download PDF
36. Integration of ChREBP-Mediated Glucose Sensing into Whole Body Metabolism.
- Author
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Baraille F, Planchais J, Dentin R, Guilmeau S, and Postic C
- Subjects
- Adipose Tissue metabolism, Adipose Tissue pathology, Animals, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Fatty Acids metabolism, Humans, Insulin Resistance, Liver metabolism, Liver pathology, Neoplasms metabolism, Neoplasms pathology, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Protein Isoforms, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Energy Metabolism, Glucose metabolism, Signal Transduction
- Abstract
Since glucose is the principal energy source for most cells, many organisms have evolved numerous and sophisticated mechanisms to sense glucose and respond to it appropriately. In this context, cloning of the carbohydrate responsive element binding protein has unraveled a critical molecular link between glucose metabolism and transcriptional reprogramming induced by glucose. In this review, we detail major findings that have advanced our knowledge of glucose sensing., (©2015 Int. Union Physiol. Sci./Am. Physiol. Soc.)
- Published
- 2015
- Full Text
- View/download PDF
37. Lipid-rich diet enhances L-cell density in obese subjects and in mice through improved L-cell differentiation.
- Author
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Aranias T, Grosfeld A, Poitou C, Omar AA, Le Gall M, Miquel S, Garbin K, Ribeiro A, Bouillot JL, Bado A, Brot-Laroche E, Clément K, Leturque A, Guilmeau S, and Serradas P
- Abstract
The enterohormone glucagon-like peptide-1 (GLP-1) is required to amplify glucose-induced insulin secretion that facilitates peripheral glucose utilisation. Alteration in GLP-1 secretion during obesity has been reported but is still controversial. Due to the high adaptability of intestinal cells to environmental changes, we hypothesised that the density of GLP-1-producing cells could be modified by nutritional factors to prevent the deterioration of metabolic condition in obesity. We quantified L-cell density in jejunum samples collected during Roux-en-Y gastric bypass in forty-nine severely obese subjects analysed according to their fat consumption. In mice, we deciphered the mechanisms by which a high-fat diet (HFD) makes an impact on enteroendocrine cell density and function. L-cell density in the jejunum was higher in obese subjects consuming >30 % fat compared with low fat eaters. Mice fed a HFD for 8 weeks displayed an increase in GLP-1-positive cells in the jejunum and colon accordingly to GLP-1 secretion. The regulation by the HFD appears specific to GLP-1-producing cells, as the number of PYY (peptide YY)-positive cells remained unchanged. Moreover, genetically obese ob/ob mice did not show alteration of GLP-1-positive cell density in the jejunum or colon, suggesting that obesity per se is not sufficient to trigger the mechanism. The higher L-cell density in HFD-fed mice involved a rise in L-cell terminal differentiation as witnessed by the increased expression of transcription factors downstream of neurogenin3 (Ngn3). We suggest that the observed increase in GLP-1-positive cell density triggered by high fat consumption in humans and mice might favour insulin secretion and therefore constitute an adaptive response of the intestine to balance diet-induced insulin resistance.
- Published
- 2015
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- View/download PDF
38. Gastric bypass surgery in NASH: a major modulator of hepatic mitochondrial dysfunction.
- Author
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Baraille F, Guilmeau S, and Postic C
- Subjects
- Animals, Humans
- Published
- 2015
- Full Text
- View/download PDF
39. Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice.
- Author
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Tavernier A, Cavin JB, Le Gall M, Ducroc R, Denis RG, Cluzeaud F, Guilmeau S, Sakar Y, Barbot L, Kapel N, Le Beyec J, Joly F, Chua S, Luquet S, and Bado A
- Subjects
- Animals, Blotting, Western, Body Composition, Body Weight, Cell Proliferation, Cells, Cultured, Energy Intake, Female, Glucose Transport Proteins, Facilitative genetics, Glucose Transporter Type 2 genetics, Glucose Transporter Type 5, Immunoenzyme Techniques, Intestinal Mucosa pathology, Leptin metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptide Transporter 1, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Symporters genetics, Diet, High-Fat adverse effects, Glucose Transport Proteins, Facilitative metabolism, Glucose Transporter Type 2 metabolism, Intestinal Mucosa metabolism, Obesity etiology, Receptors, Leptin physiology, Symporters metabolism
- Abstract
The importance of B-isoform of leptin receptor (LEPR-B) signaling in the hypothalamus, pancreas, or liver has been well characterized, but in the intestine, a unique site of entry for dietary nutrition into the body, it has been relatively ignored. To address this question, we characterized a mouse model deficient for LEPR-B specifically in intestinal epithelial cells (IECs). (IEC)LEPR-B-knockout (KO) and wild-type (WT) mice were generated by Cre-Lox strategy and fed a normal or high-fat diet (HFD). The analyses of the animals involved histology and immunohistochemistry of intestinal mucosa, indirect calorimetric measurements, whole-body composition, and expression and activities of nutrient transporters. (IEC)LEPR-B-KO mice exhibited a 2-fold increase in length of jejunal villi and have normal growth on a normal diet but were less susceptible (P<0.01) to HFD-induced obesity. No differences occurred in energy intake and expenditure between (IEC)LEPR-B-WT and -KO mice, but (IEC)LEPR-B-KO mice fed an HFD showed increased excreted fats (P<0.05). Activities of the Na(+)/glucose cotransporter SGLT-1 and GLUT2 were unaffected in LEPR-B-KO jejunum, while GLUT5-mediated fructose transport and PepT1-mediated peptide transport were substantially reduced (P<0.01). These data demonstrate that intestinal LEPR-B signaling is important for the onset of diet-induced obesity. They suggest that intestinal LEPR-B could be a potential per os target for prevention against obesity., (© FASEB.)
- Published
- 2014
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40. Novel insights into ChREBP regulation and function.
- Author
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Filhoulaud G, Guilmeau S, Dentin R, Girard J, and Postic C
- Subjects
- Animals, Apoptosis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors chemistry, Cell Proliferation, Humans, Insulin Resistance, Insulin-Secreting Cells cytology, Muscle, Skeletal metabolism, Phosphorylation, Protein Processing, Post-Translational, Protein Structure, Tertiary, Response Elements, Adipose Tissue metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Glycolysis, Insulin-Secreting Cells metabolism, Lipogenesis, Liver metabolism, Models, Biological
- Abstract
Glucose is an energy source that also controls the expression of key genes involved in energetic metabolism through the glucose-signaling transcription factor carbohydrate response element-binding protein (ChREBP). ChREBP has recently emerged as a central regulator of glycolysis and de novo fatty acid synthesis in liver, but new evidence shows that it plays a broader and crucial role in various processes, ranging from glucolipotoxicity to apoptosis and/or proliferation in specific cell types. However, several aspects of ChREBP activation by glucose metabolites are currently controversial, as well as the effects of activating or inhibiting ChREBP, on insulin sensitivity, which might depend on genetic, dietary or environmental factors. Thus, much remains to be elucidated. Here, we summarize our current understanding of the regulation and function of this fascinating transcription factor., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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41. Notch signaling and intestinal cancer.
- Author
-
Guilmeau S
- Subjects
- Animals, Humans, Signal Transduction, Intestinal Neoplasms metabolism, Intestinal Neoplasms pathology, Receptors, Notch metabolism
- Abstract
In recent years, a substantial body of evidence has accumulated to support the notion that signaling pathways known to be important during embryonic development play important roles in regulating self-renewing tissues and tumorigenesis. In this context, Notch signaling is now recognized as essential for maintaining progenitor/ stem cell population as well as for regulating cell lineage differentiation in the normal intestinal mucosa. Many studies have also showed that Notch signaling is constitutively activated in colorectal cancer and its inhibition is able to suppress the cell growth and sensitize cancer cells to treatment-induced apoptosis. Therefore, discovery of the role of γ-secretase in the Notch signaling activation has prompted intensive research on the potential use of γ-secretase inhibitors in the treatment of colon cancer. This chapter reviews the current understanding and research findings of the role of Notch signaling in intestinal homeostasis and colorectal cancer and discusses the possible Notch targeting approaches as novel molecular therapy for intestinal cancer.
- Published
- 2012
- Full Text
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42. Proteomic changes during intestinal cell maturation in vivo.
- Author
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Chang J, Chance MR, Nicholas C, Ahmed N, Guilmeau S, Flandez M, Wang D, Byun DS, Nasser S, Albanese JM, Corner GA, Heerdt BG, Wilson AJ, Augenlicht LH, and Mariadason JM
- Subjects
- Animals, Coloring Agents, Electrophoresis, Gel, Two-Dimensional, Endoplasmic Reticulum Chaperone BiP, Enzymes chemistry, Enzymes genetics, Enzymes isolation & purification, Gene Expression Regulation, Intestinal Mucosa chemistry, Intestinal Mucosa cytology, Intestine, Small chemistry, Intestine, Small cytology, Lipids physiology, Mice, Proteins chemistry, Proteins genetics, Proteins isolation & purification, Rats, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Steroids metabolism, Intestinal Mucosa physiology, Intestine, Small physiology, Proteomics
- Abstract
Intestinal epithelial cells undergo progressive cell maturation as they migrate along the crypt-villus axis. To determine molecular signatures that define this process, proteins differentially expressed between the crypt and villus were identified by 2D-DIGE and MALDI-MS. Forty-six differentially expressed proteins were identified, several of which were validated by immunohistochemistry. Proteins upregulated in the villus were enriched for those involved in brush border assembly and lipid uptake, established features of differentiated intestinal epithelial cells. Multiple proteins involved in glycolysis were also upregulated in the villus, suggesting increased glycolysis is a feature of intestinal cell differentiation. Conversely, proteins involved in nucleotide metabolism, and protein processing and folding were increased in the crypt, consistent with functions associated with cell proliferation. Three novel paneth cell markers, AGR2, HSPA5 and RRBP1 were also identified. Notably, significant correlation was observed between overall proteomic changes and corresponding gene expression changes along the crypt-villus axis, indicating intestinal cell maturation is primarily regulated at the transcriptional level. This proteomic profiling analysis identified several novel proteins and functional processes differentially induced during intestinal cell maturation in vivo. Integration of proteomic, immunohistochemical, and parallel gene expression datasets demonstrate the coordinated manner in which intestinal cell maturation is regulated.
- Published
- 2008
- Full Text
- View/download PDF
43. Intestinal deletion of Pofut1 in the mouse inactivates notch signaling and causes enterocolitis.
- Author
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Guilmeau S, Flandez M, Bancroft L, Sellers RS, Tear B, Stanley P, and Augenlicht LH
- Subjects
- Animals, Bacterial Translocation, Cell Fractionation, Enterocolitis pathology, Fatty Acid-Binding Proteins metabolism, Fucosyltransferases genetics, Gene Silencing, High Mobility Group Proteins metabolism, Intestinal Mucosa microbiology, Intestinal Mucosa pathology, Ligands, Lymph Nodes microbiology, Mice, Mice, Transgenic, SOX9 Transcription Factor, Tissue Culture Techniques, Transcription Factors metabolism, Galactoside 2-alpha-L-fucosyltransferase, Enterocolitis metabolism, Fucosyltransferases metabolism, Intestinal Mucosa metabolism, Receptors, Notch metabolism, Signal Transduction
- Abstract
Background & Aims: Notch downstream targets are fundamental to intestinal cell lineage commitment and are suggested as therapeutic targets for colon cancer cells. However, the role of endogenous Notch signaling through receptor-ligand interaction, and effects of its longer term down-regulation on intestinal homeostasis, are unclear., Methods: To address these issues, the gene encoding protein O-fucosyltransferase 1, an enzyme required for Notch ligand binding and thus activation of all Notch receptors, was deleted in the mouse intestinal and colonic epithelium, through Villin-Cre-mediated recombination., Results: Pofut1 deletion inactivated Notch signaling, giving rise to smaller but viable mice. These mice exhibited a large increase in all intestinal secretory cell lineages, which accumulated in the crypts, resulting in crypt hyperplasia. Although proliferating cells were largely reduced in the colon, the transit amplifying compartment was maintained in the upper crypts of the intestinal mucosa. By 9 months, these perturbations in cell maturation altered mucus-associated gut microbiota and caused chronic intestinal inflammation, with evidence of bacterial translocation to the mesenteric lymph nodes, macrophage, and T-lymphocyte infiltration, and Th1/Th17 immune response. Dysplastic foci were also observed in Pofut1-deficient small intestine with occasional progression to tumor formation., Conclusions: Mucus hypersecretion upon Pofut1 inactivation is accompanied by alteration of the mucus-associated flora, which likely contributes to the development of enterocolitis. Therefore, these data identify important potential complications in strategies to target Notch signaling in therapeutic approaches to colon cancer.
- Published
- 2008
- Full Text
- View/download PDF
44. p27kip1 Regulates cdk2 activity in the proliferating zone of the mouse intestinal epithelium: potential role in neoplasia.
- Author
-
Smartt HJ, Guilmeau S, Nasser SV, Nicholas C, Bancroft L, Simpson SA, Yeh N, Yang W, Mariadason JM, Koff A, and Augenlicht LH
- Subjects
- Animals, Cell Division physiology, Cell Line, Tumor, Colonic Neoplasms metabolism, Cyclin D, Cyclin E metabolism, Cyclin-Dependent Kinase 4 metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cyclin-Dependent Kinase Inhibitor p27 genetics, Cyclins metabolism, Female, G1 Phase physiology, Genotype, Homeostasis physiology, Humans, Intestinal Mucosa metabolism, Male, Mice, Mice, Mutant Strains, S Phase physiology, Colonic Neoplasms pathology, Cyclin-Dependent Kinase 2 metabolism, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Intestinal Mucosa pathology
- Abstract
Background & Aims: Reduced p27(kip1) expression is a marker of poor prognosis in colorectal neoplasia, and inactivation of p27 in mice (p27(Delta51/Delta51)) causes increased intestinal epithelial cell proliferation and small and large intestinal neoplasia in a diet-dependent manner. Here, we addressed the role of p27 in untransformed intestinal epithelial cells in vivo and the consequence of its targeted inactivation., Methods: A sequential fractionation procedure was used to isolate murine intestinal epithelial cells relative to their position along the crypt-villus axis, and the levels of cyclins, cyclin-dependent kinases (cdks), and cdk inhibitors and of the complexes formed among them was determined by immunoprecipitation-immunoblotting and kinase assays., Results: As cells exited the proliferative crypt compartment, expression and activity of both cdk2 and cdk4 decreased, in parallel with reduced expression of cyclin A and proliferating cell nuclear antigen (PCNA); expression of cyclin D1, D2, and cyclin E showed little change. As expected, expression of the cdk inhibitors p21, p57, and p16 was highest in differentiated villus cells. Unexpectedly, p27 protein expression was highest in cells of the proliferative crypt compartment where it bound both cdk2 and cdk4. Cdk2 activity was increased in crypt cells from p27(Delta51/Delta51) mice, although cyclin D-associated kinase activity was unchanged (indeed, cyclin D1/2-cdk4 complex levels were reduced). Importantly, cdk2 activity was unchanged in crypt cells from p21(-/-) mice, which do not develop intestinal tumors., Conclusions: We propose that p27 contributes to intestinal epithelial homeostasis by regulating cdk2 activity in proliferating cells, thus gating cell cycle progression and suppressing intestinal neoplasia.
- Published
- 2007
- Full Text
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45. Luminal leptin activates mucin-secreting goblet cells in the large bowel.
- Author
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Plaisancie P, Ducroc R, El Homsi M, Tsocas A, Guilmeau S, Zoghbi S, Thibaudeau O, and Bado A
- Subjects
- Animals, Cells, Cultured, Colon drug effects, Dose-Response Relationship, Drug, Enteral Nutrition, Goblet Cells drug effects, HT29 Cells, Humans, Male, Mice, Perfusion, Rats, Rats, Wistar, Colon metabolism, Goblet Cells metabolism, Leptin administration & dosage, Mucins metabolism
- Abstract
Leptin has been suggested to be involved in tissue injury and/or mucosal defence mechanisms. Here, we studied the effects of leptin on colonic mucus secretion and rat mucin 2 (rMuc2) expression. Wistar rats and ob/ob mice were used. Secretion of mucus was followed in vivo in the rat perfused colon model. Mucus secretion was quantified by ELISA, and rMuc2 mRNA levels were quantified by real-time RT PCR. The effects of leptin alone or in association with protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) inhibitors on mucin secreted by human mucus-secreting HT29-MTX cells were determined. Leptin was detected in the rat colonic lumen at substantial levels. Luminal perfusion of leptin stimulates mucus-secreting goblet cells in a dose-dependent manner in vivo in the rat. Leptin (10 nmol/l) increased mucus secretion by a factor of 3.5 and doubled rMuc2 mRNA levels in the colonic mucosa. There was no damage to mucosa 24 h after leptin, but the number of stained mucus cells significantly increased. Leptin-deficient ob/ob mice have abnormally dense mucus-filled goblet cells. In human colonic goblet-like HT29-MTX cells expressing leptin receptors, leptin increased mucin secretion by activating PKC- and PI3K-dependent pathways. This is the first demonstration that leptin, acting from the luminal side, controls the function of mucus-secreting goblet cells. Because the gel layer formed by mucus at the surface of the intestinal epithelium has a barrier function, our data may be relevant physiologically in defence mechanisms of the gastrointestinal tract.
- Published
- 2006
- Full Text
- View/download PDF
46. Leptin and Ob-Rb receptor isoform in the human digestive tract during fetal development.
- Author
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Aparicio T, Kermorgant S, Darmoul D, Guilmeau S, Hormi K, Mahieu-Caputo D, and Lehy T
- Subjects
- Amniotic Fluid chemistry, DNA biosynthesis, Esophagus chemistry, Fetal Development, Humans, Immunohistochemistry, Intestines chemistry, Leptin physiology, Protein Isoforms, Receptors, Cell Surface physiology, Receptors, Leptin, Reverse Transcriptase Polymerase Chain Reaction, Stomach chemistry, Fetus chemistry, Leptin analysis, Receptors, Cell Surface analysis
- Abstract
Context: Leptin, partially produced by the stomach, is a hormone involved in energy balance and regulation of food intake. It also regulates some digestive functions through its functional receptor Ob-Rb expressed by gastrointestinal epithelial cells., Objective: The objective of the study was to investigate the temporal and spatial appearance of Ob-Rb in the human digestive tract and leptin in the stomach., Design: The esophagus, stomach, and intestine samples of 7- to 24-wk-old human fetuses and adult mucosae were studied by RT-PCR, immunohistochemistry, and Western blot. Leptin was measured by RIA in amniotic fluids at 16-33 wk gestation., Results: All mucosae expressed Ob-Rb (mRNA and/or protein) between 7 and 9 wk gestation. Leptin protein appeared by 8 wk in the gastric mucosa, whereas leptin mRNA was detected around 11 wk. Leptin levels in amniotic fluids were significantly higher during the second than during the third trimester. Overall, Ob-Rb immunoreactivity was higher in young fetuses, during the period corresponding to the formation of gastric buds and primitive intestinal crypts and the beginning of differentiation of epithelial cell types, than in the oldest. Leptin added to culture medium of gastrointestinal explants from 10- to 12-wk-old fetuses appeared to affect DNA synthesis as compared with controls, indicating that leptin receptor functionality was developing., Conclusions: The strong expression of leptin, in amniotic fluid when fetuses begin swallowing then in the gastric mucosa, and the early presence of Ob-Rb in mucosae suggest a possible role for leptin, exerted endoluminally and in a paracrine pathway, in the developmental process (growth and/or maturation) of the human digestive tract.
- Published
- 2005
- Full Text
- View/download PDF
47. Luminal leptin induces rapid inhibition of active intestinal absorption of glucose mediated by sodium-glucose cotransporter 1.
- Author
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Ducroc R, Guilmeau S, Akasbi K, Devaud H, Buyse M, and Bado A
- Subjects
- Acetophenones pharmacology, Animals, Benzopyrans pharmacology, Enzyme Inhibitors pharmacology, Intestinal Absorption drug effects, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Kinetics, Leptin physiology, Male, Membrane Glycoproteins antagonists & inhibitors, Membrane Potentials drug effects, Membrane Potentials physiology, Monosaccharide Transport Proteins antagonists & inhibitors, Obesity, Rats, Rats, Wistar, Rats, Zucker, Sodium-Glucose Transporter 1, Thinness, Glucose metabolism, Intestinal Absorption physiology, Leptin pharmacology, Membrane Glycoproteins metabolism, Monosaccharide Transport Proteins metabolism
- Abstract
The effect of leptin on glucose transport was studied in rat jejunal mucosa in Ussing chambers. Leptin was added in the luminal or the serosal compartment before the tissues were challenged with 1, 10, or 50 mmol/l glucose. In response to 10 mmol/l glucose, the increase in short-circuit current (DeltaIsc) reached 26.8 +/- 2.1 microA/cm(2). Luminal addition of leptin dramatically decreased glucose-induced Isc (90.5% for 10 nmol/l leptin). Inhibition was maximal after 5 min and dose dependent (IC(50) = 0.13 nM). Western blot analysis showed that rapid inhibition of glucose-induced Isc by leptin was associated with a parallel decrease in the abundance of sodium-glucose transporter-1 in brush border membranes. Inhibition by luminal leptin of DeltaIsc was prevented by inhibitor of conventional protein kinase C isoforms. Serosal addition of leptin did not decrease glucose-induced Isc within 5 min and reached maximum after 10 min. The effect of leptin from serosal side was blocked by cholecystokinin (CCK) receptor-2 receptor antagonist YM022. Altogether, these data demonstrate that luminal leptin induces rapid inhibition of glucose entry into enterocyte. The slower action of leptin on the serosal side of mucosa seems indirect and is likely mediated by endogenous CCK. They demonstrate that gut leptin is a major regulator of rapid intestinal glucose transport.
- Published
- 2005
- Full Text
- View/download PDF
48. Gastric leptin: a new manager of gastrointestinal function.
- Author
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Guilmeau S, Buyse M, and Bado A
- Subjects
- France, Gastric Mucosa metabolism, Gastrointestinal Tract drug effects, Leptin genetics, Receptors, Cell Surface drug effects, Receptors, Cell Surface metabolism, Receptors, Leptin, Gastrointestinal Tract chemistry, Gastrointestinal Tract physiology, Leptin metabolism, Leptin pharmacology
- Abstract
Leptin, a 16 kDa protein-encoded by the ob gene, is involved in the regulation of food intake, body composition and energy expenditure through a central feedback mechanism. Initially thought to be adipocyte-specific, the ob gene, as well as the leptin receptor, has been found in a variety of other tissues including the stomach. Stomach-derived leptin, mainly secreted in the lumen, remains stable in gastric juice even at pH2. It then enters the intestine where leptin receptors have been identified on the brush border. Recent data also suggest that gut leptin may act locally within the gastrointestinal tract to influence intestinal functions, such as nutrient absorption, and thus have physiopathological implications.
- Published
- 2004
- Full Text
- View/download PDF
49. Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT-29 cells via NF-kappaB signaling.
- Author
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Rouet-Benzineb P, Aparicio T, Guilmeau S, Pouzet C, Descatoire V, Buyse M, and Bado A
- Subjects
- Apoptosis drug effects, Butyrates pharmacology, Cell Line, Tumor, Colonic Neoplasms pathology, Drug Antagonism, Humans, Leptin pharmacology, Signal Transduction physiology, Apoptosis physiology, Colonic Neoplasms metabolism, Leptin metabolism, NF-kappa B metabolism
- Abstract
This study shows that leptin induced a rapid phosphorylation of p42/44 mitogen-activated protein kinase, an enhancement of both NF-kappaB DNA binding and transcriptional activities, and a concentration-dependent increase of HT-29 cell proliferation. These effects are consistent with the presence of leptin receptors on cell membranes. The leptin induction of cell growth was associated with an increase of cell population in S and G2/M phase compared with control cells found in G0/G1 phase of the cell cycle. Moreover, cyclin D1 immunoreactivity was enhanced in leptin-treated HT-29 cells and this increase was essentially associated with cell population in G0/G1 phase. On the other hand, we observed that sodium butyrate inhibited cell proliferation by blocking HT-29 cells in G0/G1 phase of the cell cycle. Interestingly, at physiological concentration, leptin prevented sodium butyrate-induced morphological nucleus changes, DNA laddering and suppressed butyrate-induced cell cycle arrest. This anti-apoptotic effect of leptin was associated with HT-29 cell proliferation and activation NF-kappaB pathways. However, the phosphorylation of p42/44 MAP kinase in response to leptin was reduced in butyrate-treated cells. These data demonstrated that leptin is a potent mitogenic factor for intestinal epithelial cells through the MAP kinase and NF-kappaB pathways. They also showed, for the first time, that leptin promotes colon cancer HT-29 cell survival upon butyrate challenge by counteracting the apoptotic programs initiated by this short chain fatty acid probably through the NF-kappaB pathways. Although further studies are required to unravel the precise mechanism, these data may have significance in the pathogenesis of colorectal cancer and ulcerative colitis diseases.
- Published
- 2004
- Full Text
- View/download PDF
50. [Paracrine actions of the stomach-derived leptin].
- Author
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Buyse M, Aparicio T, Guilmeau S, Goïot H, Sobhani I, and Bado A
- Subjects
- Animals, Colitis physiopathology, Humans, Intestinal Absorption physiology, Leptin genetics, Leptin physiology, Stomach physiology
- Abstract
Leptin, a 16 kilodalton protein-encoded by the ob gene, is involved in the regulation of food intake, body composition, and energy expenditure through a central feedback mechanism. Initially thought to be adipocyte-specific, the ob gene, as well as the leptin receptor, has been found in a variety of other tissues. Relevant to this review, the leptin gene and its receptor have been identified in the stomach, intestine, liver, and pancreas. Recent data also suggest that gut leptin may act locally within the gastrointestinal tract to influence intestinal functions such as nutrient absorption and may have a physiopathological implication. This review emphasises the concept that leptin may be a new gastrointestinal hormone.
- Published
- 2004
- Full Text
- View/download PDF
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