TNF signaling impacts glucagon-like peptide-1 expression and secretion

in Journal of Molecular Endocrinology
Correspondence should be addressed to Z Ying: yingzhekang@hotmail.com or zying@medicine.umaryland.edu
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Numerous studies have implicated tumor necrosis factor α (TNFα) in the pathogenesis of type 2 diabetes. However, the role of its primary receptor, TNF receptor 1 (TNFR1), in homeostatic regulation of glucose metabolism is still controversial. In addition to TNFα, lymphotoxin α (LTα) binds to and activates TNFR1. Thus, TNFα and LTα together are known as TNF. To delineate the role of TNF signaling in glucose homeostasis, the present study ascertained how TNF signaling deficiency affects major regulatory components of glucose homeostasis. To this end, normal diet-fed male TNFR1-deficient mice (TNFR1−/−), TNFα/LTα/LTβ triple-deficient mice (TNF/LT∆3) and their littermate controls were subjected to intraperitoneal glucose tolerance test, insulin tolerance test and oral glucose tolerance test. The present results showed that TNFR1−/− and TNF/LT∆3 mice vs their controls had comparable body weight, tolerance to intraperitoneal glucose and sensitivity to insulin. However, their tolerance to oral glucose was significantly increased. Additionally, glucose-induced insulin secretion assessments revealed that TNFR1 or TNF/LT deficiency significantly increased oral but not intraperitoneal glucose-induced insulin secretion. Consistently, qPCR and immunohistochemistry analyses showed that TNFR1−/− and TNF/LT∆3 mice vs their controls had significantly increased ileal expression of glucagon-like peptide-1 (GLP-1), one of the primary incretins. Their oral glucose-induced secretion of GLP-1 was also significantly increased. These data collectively suggest that physiological TNF signaling regulates glucose metabolism primarily through effects on GLP-1 expression and secretion and subsequently insulin secretion.

 

      Society for Endocrinology

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    TNF signaling deficiency increases mouse tolerance to orally gavaged but not intraperitoneally injected glucose. (A, B and C) TNFR1−/− and littermate controls (10–16 weeks old, n = 5/group) were subjected to IPGTT (A), ITT (B) and OGTT (C). The area under curve (AUC) of OGTT was presented in the inset. (D, E and F) TNF/LT∆3 and littermate controls (10–18 weeks old, n = 6/group) were subjected to IPGTT (D), ITT (E) and OGTT (F). The AUC of OGTT was presented in the inset. *P < 0.05 vs litter controls (WT), two-way ANOVA or student’s t test (AUC).

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    TNF signaling deficiency increases orally gavaged but not intraperitoneally injected glucose-induced insulin secretion. (A and B) TNFR1 / and littermate controls (10–16 weeks old, n=5/group) were subjected to IPGTT (A) or OGTT (B). Serum insulin levels at the indicated time-points were determined by ELISA. (C and D) TNF/LT∆3 and littermate controls (10–18 weeks old, n=6/group) were subjected to IPGTT (C) or OGTT (D). Serum insulin levels at the indicated time-points were determined by ELISA. *P < 0.05 vs litter controls (WT), two-way ANOVA.

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    TNF signaling deficiency increases ileal GLP-1 mRNA expression. The duodenal and ileal villi were isolated from 16-h-fasted TNFR1 / and littermate controls (A and B, 14–20 weeks old, n=5/group) or TNF/LT∆3 and littermate controls (C and D, 14–22 weeks old, n=6/group) and subjected to assessment of GLP-1 and GIP mRNA expression by real-time qPCR. *P < 0.05 vs litter controls (WT), Student t test.

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    TNF signaling deficiency increases ileal GLP-1 protein expression. The ileum was isolated from 16-h-fasted TNFR1 / and littermate controls (A, B and C, 14–20 weeks old, n=5/group) or TNF/LT∆3 and littermate controls (D, E and F, 14–22 weeks old, n=6/group) and subjected to immunohistochemistry using anti-GLP-1 antibody. (A and D) The representative images. Scale bar, 100 µm. Insets, 8× magnified GLP-1+ cell. The yellow arrow marks another GLP-1+ cell. B and E, the number of GLP-1+ cells per µm2 ileal tissue. (C and F) The quantitation of immunohistochemistry signal. *P < 0.05 vs litter controls (WT), Student t test. No immunostaining signal was detected in negative controls and thus was not shown. A full color version of this figure is available at https://doi.org/10.1530/JME-18-0129.

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    TNF signaling deficiency increases orally gavaged glucose-induced secretion of GLP-1 but not GIP. (A and B) TNFR1 / and littermate controls (9–17 weeks old, n=5/group) were orally gavaged with glucose (2 g/kg body weight) and then killed at the indicated time-points. The plasma were harvested, and their GLP-1 (A) and GIP (B) levels were assessed by ELISA. *P < 0.05 vs litter controls (WT), two-way ANOVA. (C and D) TNF/LT∆3 and littermate controls (8–11 weeks old, n=5/group) were orally gavaged with glucose (2 g/kg body weight) and then killed at the indicated time-points. The plasma were harvested, and their GLP-1 (C) and GIP (D) levels were assessed by ELISA. *P < 0.05 vs litter controls (WT), two-way ANOVA.

References

  • Al-LamkiRSMayadasTN 2015 TNF receptors: signaling pathways and contribution to renal dysfunction. Kidney International 87 281296. (https://doi.org/10.1038/ki.2014.285)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AntonopoulosASPapanikolaouEVogiatziGOikonomouETousoulisD 2017 Anti-inflammatory agents in peripheral arterial disease. Current Opinion in Pharmacology 39 18. (https://doi.org/10.1016/j.coph.2017.11.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • DruckerDJ 2018 Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metabolism 27 740756. (https://doi.org/10.1016/j.cmet.2018.03.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • EverardACaniPD 2014 Gut microbiota and GLP-1. Reviews in Endocrine and Metabolic Disorders 15 189196. (https://doi.org/10.1007/s11154-014-9288-6)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GagnonJSauveMZhaoWStaceyHMWiberSCBolzSSBrubakerPL 2015 Chronic exposure to TNFalpha impairs secretion of glucagon-like peptide-1. Endocrinology 156 39503960. (https://doi.org/10.1210/en.2015-1361)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GubernatorovaEOTumanovAV 2016 Tumor necrosis factor and lymphotoxin in regulation of intestinal inflammation. Biochemistry 81 13091325. (https://doi.org/10.1134/S0006297916110092)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • HotamisligilGS 2017 Inflammation, metaflammation and immunometabolic disorders. Nature 542 177185. (https://doi.org/10.1038/nature21363)

  • HotamisligilGSShargillNSSpiegelmanBM 1993 Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259 8791. (https://doi.org/10.1126/science.7678183)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HuZChenMZhouHTharakanAWangXQiuLLiangSQinXZhangYWangWet al. 2017 Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM2.5. Toxicology 390 100108. (https://doi.org/10.1016/j.tox.2017.09.009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • JangHJKokrashviliZTheodorakisMJCarlsonODKimBJZhouJKimHHXuXChanSLJuhaszovaMet al. 2007 Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. PNAS 104 1506915074. (https://doi.org/10.1073/pnas.0706890104)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KuprashDVTumanovAVLiepinshDJKorolevaEPDrutskayaMSKruglovAAShakhovANSouthonEMurphyWJTessarolloLet al. 2005 Novel tumor necrosis factor-knockout mice that lack Peyer’s patches. European Journal of Immunology 35 15921600. (https://doi.org/10.1002/eji.200526119)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiJFrederickA-LKimY-CWoodRJLiuZ 2016 Genetic ablation of TNF-α attenuates high fat diet-induced obesity potentially via diminishing wnt-signaling and determinant genes of adipogenesis. FASEB Journal 30 431.433431.433. (https://doi.org/10.1096/fj.201600694R)

    • Search Google Scholar
    • Export Citation
  • LiuCFengXLiQWangYHuaM 2016 Adiponectin, TNF-alpha and inflammatory cytokines and risk of type 2 diabetes: a systematic review and meta-analysis. Cytokine 86 100109. (https://doi.org/10.1016/j.cyto.2016.06.028)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MartinsLBOliveiraMCMenezes-GarciaZRodriguesDFLanaJPVieiraLQTeixeiraMMFerreiraAVM 2017 Paradoxical role of tumor necrosis factor on metabolic dysfunction and adipose tissue expansion in mice. Nutrition 50 17. (https://doi.org/10.1016/j.nut.2017.07.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • NauckMAMeierJJ 2016 The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes and Endocrinology 4 525536. (https://doi.org/10.1016/S2213-8587(15)00482-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • PelusoIPalmeryM 2016 The relationship between body weight and inflammation: lesson from anti-TNF-alpha antibody therapy. Human Immunology 77 4753. (https://doi.org/10.1016/j.humimm.2015.10.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ProbertL 2015 TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302 222. (https://doi.org/10.1016/j.neuroscience.2015.06.038)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RajaniCJiaW 2018 Disruptions in gut microbial-host co-metabolism and the development of metabolic disorders. Clinical Science 132 791811. (https://doi.org/10.1042/CS20171328)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SeinoYFukushimaMYabeD 2010 GIP and GLP-1, the two incretin hormones: similarities and differences. Journal of Diabetes Investigation 1 823. (https://doi.org/10.1111/j.2040-1124.2010.00022.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SvendsenBHolstJJ 2016 Regulation of gut hormone secretion. Studies using isolated perfused intestines. Peptides 77 4753. (https://doi.org/10.1016/j.peptides.2015.08.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TaylorSI 2018 GLP-1 receptor agonists: differentiation within the class. Lancet Diabetes and Endocrinology 6 8385. (https://doi.org/10.1016/S2213-8587(17)30413-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • TodaKHayashiYSaibaraT 2010 Deletion of tumor necrosis factor-alpha receptor type 1 exacerbates insulin resistance and hepatic steatosis in aromatase knockout mice. Biochimica et Biophysica Acta 1801. 655664. (https://doi.org/10.1016/j.bbalip.2010.03.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TsiotraPCTsigosCRaptisSA 2001 TNFalpha and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells. International Journal of Obesity and Related Metabolic Disorders 25 10181026. (https://doi.org/10.1038/sj.ijo.0801657)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • VentreJDoebberTWuMMacNaulKStevensKPasparakisMKolliasGMollerDE 1997 Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. Diabetes 46 15261531. (https://doi.org/10.2337/diab.46.9.1526)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • VinayDSKwonBS 2012 Targeting TNF superfamily members for therapeutic intervention in rheumatoid arthritis. Cytokine 57 305312. (https://doi.org/10.1016/j.cyto.2011.12.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhangSKimKH 1995 TNF-alpha inhibits glucose-induced insulin secretion in a pancreatic beta-cell line (INS-1). FEBS Letters 377 237239. (https://doi.org/10.1016/0014-5793(95)01272-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ZhaoLZhangFDingXWuGLamYYWangXFuHXueXLuCMaJet al. 2018 Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 359 11511156. (https://doi.org/10.1126/science.aao5774)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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