Cell and Tissue Biology

, Volume 12, Issue 1, pp 48–56 | Cite as

Enhanced Glucose Uptake in Phenylbutyric Acid-Treated 3T3-L1 Adipocytes

  • H. Fakhoury
  • S. Osman
  • N. Ghazale
  • N. Dahdah
  • M. El-Sibai
  • A. KanaanEmail author


Diabetes Mellitus is a chronic metabolic disease marked by altered glucose homeostasis and insulin resistance. The phosphatase PTEN antagonizes the insulin-induced-PI3K-driven cascade that normally leads to GLUT4 membrane translocation. This study investigates the effect of Phenylbutyric Acid (PBA), a chemical chaperone and a potential mediator of PTEN activity, on glucose uptake in differentiated 3T3-L1 adipocytes. Adipocyte differentiation status was quantified by Oil Red O staining and the expression of AP2. Baseline and insulin-induced adipocyte glucose uptake were assayed with and without PBA treatment. Expression of GLUT1, GLUT4, PIP3, pAkt, pPTEN, and PARK-7 was examined by western blot. Plasma membrane expression of GLUT4 was determined using immunofluorescence. Leptin and adiponectin secretion was measure by enzyme-linked immunosorbent assay. PBA treatment, alone or with insulin induction, significantly increased glucose uptake in 3T3-L1 adipocytes. PBA significantly increased GLUT1 but not GLUT4 total protein expression. However, a significant increase in membrane GLUT4 protein translocation was observed. The expression of PIP3 and pAkt increased indicating enhanced PI3k pathway activity. There was a significant decrease in PTEN activity as evident by a rise in the phosphorylated form of this protein. PARK7 protein expression increased with PBA. Treating differentiated adipocytes with PBA did not alter their differentiation status, but decreased the leptin to adiponectin ratio. Conclusion: this study showed that PBA enhances adipocyte glucose uptake potentially through its effect on glucose transporter expression and/or trafficking via the PI3K signaling pathway; suggesting PBA as a possible candidate for the ancillary management of diabetes.


adipocytes glucose uptake phenylbutyric acid diabetes PARK7 GLUT 


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  1. Al-Hamodi, Z., Al-Habori, M., Al-Meeri, A., and Saif-Ali, R., Association of adipokines, leptin/adiponectin ratio and C-reactive protein with obesity and type 2 diabetes mellitus, Diabetol. Metab. Syndr. eCollection, 2014, vol. 6, no. 1, p. 995–996699.CrossRefGoogle Scholar
  2. Antuna-Puente, B., Feve, B., Fellahi, S., and Bastard, J.P., Adipokines: the missing link between insulin resistance and obesity, Diabetes Metab., 2008, vol. 34, no. 1, pp. 2–11.CrossRefPubMedGoogle Scholar
  3. Basseri, S., Lhotak, S., Sharma, A.M., and Austin, R.C., The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response, J. Lipid Res., 2009, vol. 50, no. 12, pp. 2486–2501.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Berger, J., Pujol, A., Aubourg, P., and Forss-Petter, S., Current and future pharmacological treatment strategies in X-linked adrenoleukodystrophy, Brain Pathol., 2010, vol. 20, no. 4, pp. 845–856.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Carrera Boada, C.A. and Martinez-Moreno, J.M., Pathophysiology of diabetes mellitus type 2: beyond the duo “insulin resistance-secretion deficit,” Nutr. Hosp., 2013, vol. 28, suppl. 2, pp. 78–87.PubMedGoogle Scholar
  6. Chriett, S. and Pirola, L., Essential roles of four-carbon backbone chemicals in the control of metabolism, World J. Biol. Chem., 2015, vol. 6, no. 3, pp. 223–230.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chu, E.C. and Tarnawski, A.S., PTEN regulatory functions in tumor suppression and cell biology, Med. Sci. Monit., 2004, vol. 10, no. 10, pp. RA235–RA241.PubMedGoogle Scholar
  8. Cornell, S., Continual evolution of type 2 diabetes: an update on pathophysiology and emerging treatment options, Ther. Clin. Risk Manag., 2015, vol. 11, pp. 621–632.CrossRefPubMedPubMedCentralGoogle Scholar
  9. da Costa, C.A., DJ-1: a newcomer in Parkinson’s disease pathology, Curr. Mol. Med., 2007, vol. 7, no. 7, pp. 650–657.CrossRefPubMedGoogle Scholar
  10. Deshpande, A.D., Harris-Hayes, M., and Schootman, M., Epidemiology of diabetes and diabetes-related complications, Phys. Ther., 2008, vol. 88, no. 11, pp. 1254–1264.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dimitriadis, G., Mitrou, P., Lambadiari, V., Maratou, E., and Raptis, S.A., Insulin effects in muscle and adipose tissue, Diabetes Res. Clin. Pract., 2011, vol. 93, suppl. 1, pp. S52–S59.CrossRefPubMedGoogle Scholar
  12. Gao, Z., Yin, J., Zhang, J., Ward, R.E., Martin, R.J., Lefevre, M., et al., Butyrate improves insulin sensitivity and increases energy expenditure in mice, Diabetes, 2009, vol. 58, no. 7, pp. 1509–1517.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Ge, X., Chen, C., Hui, X., Wang, Y., Lam, K.S.L, and Xu, A., Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes, J. Biol. Chem., 2011, vol. 286, no. 40, pp. 34533–34541.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gould, G.W. and Holman, G.D., The glucose transporter family: structure, function and tissue-specific expression, Biochem. J., 1993, vol. 295, pt. 2, pp. 329–341.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Govers, R., Coster, A.C., and James, D.E., Insulin increases cell surface GLUT4 levels by dose dependently discharging GLUT4 into a cell surface recycling pathway, Mol. Cell. Biol., 2004, vol. 24, no. 14, pp. 6456–6466.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Haque, M.S., Minokoshi, Y., Hamai, M., Iwai, M., Horiuchi, M., and Shimazu, T., Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats, Diabetes, 1999, vol. 48, no. 9, pp. 1706–1712.CrossRefPubMedGoogle Scholar
  17. Hauner, H., Roèhrig, K., Spelleken, M., and Liu, L.S. and Eckel, J., Development of insulin-responsive glucose uptake and GLUT4 expression in differentiating human adipocyte precursor cells, Int. J. Obes., 1998, vol. 22, 448–453.CrossRefGoogle Scholar
  18. Hu, H., Li, L., Wang, C., He, H., Mao, K., Ma, X., et al., 4-phenylbutyric acid increases GLUT4 gene expression through suppression of HDAC5 but not endoplasmic reticulum stress, Cell Physiol. Biochem., 2014, vol. 33, no. 6, pp. 1899–1910.CrossRefPubMedGoogle Scholar
  19. Iannitti, T. and Palmieri, B., Clinical and experimental applications of sodium phenylbutyrate, Drugs, 2011, vol. RD 11, no. 3, pp. 227–249.Google Scholar
  20. Jain, D., Jain, R., Eberhard, D., Eglinger, J., Bugliani, M., Piemonti, L., et al., Age- and diet-dependent requirement of DJ-1 for glucose homeostasis in mice with implications for human type 2 diabetes, J. Mol. Cell Biol., 2012, vol. 4, no. 4, pp. 221–230.CrossRefPubMedGoogle Scholar
  21. Kamohara, S., Burcelin, R., Halaas, J.L., Friedman, J.M., and Charron, M.J., Acute stimulation of glucose metabolism in mice by leptin treatment, Nature, 1997, vol. 389, no. 6649, pp. 374–377.CrossRefPubMedGoogle Scholar
  22. Karylowski, O., Zeigerer, A., Cohen, A., and McGraw, T.E., GLUT4 is retained by an intracellular cycle of vesicle formation and fusion with endosomes, Mol. Biol. Cell, 2004, vol. 15, no. 2, pp. 870–882.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kim, R.H., Peters, M., Jang, Y., Shi, W., Pintilie, M., Fletcher, G.C., et al., DJ-1, a novel regulator of the tumor suppressor PTEN, Cancer Cell, 2005, vol. 7, no. 3, pp. 263–273.CrossRefPubMedGoogle Scholar
  24. Kim, Y.C., Kitaura, H., Taira, T., Iguchi-Ariga, S.M, and Ariga, H., Oxidation of DJ-1-dependent cell transformation through direct binding of DJ-1 to PTEN, Int. J. Oncol., 2009, vol. 35, no. 6, pp. 1331–1341.CrossRefPubMedGoogle Scholar
  25. Kim, J.M., Jang, H.J., Choi, S.Y., Park, S.A., Kim, I.S., Yang, Y.R., et al., DJ-1 contributes to adipogenesis and obesity-induced inflammation, Sci. Rep., 2014, vol. 4, p. 4805.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Li, J., Houseknecht, K.L., Stenbit, A.E., Katz, E.B., and Charron, M.J., Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice, FASEB J., 2000, vol. 14, no. 9, pp. 1117–1125.CrossRefPubMedGoogle Scholar
  27. Lin, H.V., Ren, H., Samuel, V.T., Lee, H.Y., Lu, T.Y., Shulman, G.I., et al., Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues, Diabetes, 2011, vol. 60, no. 3, pp. 700–709.CrossRefPubMedPubMedCentralGoogle Scholar
  28. McGee, S.L., van Denderen, B.J., Howlett, K.F., Mollica, J., Schertzer, J.D., Kemp, B.E., et al., AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5, Diabetes, 2008, vol. 57, no. 4, pp. 860–867.CrossRefPubMedGoogle Scholar
  29. Minokoshi, Y., Haque, M.S., and Shimazu, T., Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats, Diabetes, 1999, vol. 48, no. 2, pp. 287–291.CrossRefPubMedGoogle Scholar
  30. Nugent, C., Prins, J.B., Whitehead, J.P., Savage, D., Wentworth, J.M., Chatterjee, V.K., et al., Potentiation of glucose uptake in 3T3-L1 adipocytes by PPAR agonists is maintained in cells expressing a PPAR dominant-negative mutant: evidence for selectivity in the downstream responses to PPAR activation, Mol. Endocrinol., 2001, vol. 15, no. 10, pp. 1729–1738.PubMedGoogle Scholar
  31. Ozcan, U., Yilmaz, E., Ozcan, L., Furuhashi, M., Vaillancourt, E., Smith, R.O., et al., Chemical chaperones reduce ERstress and restore glucose homeostasis in a mouse model of type 2 diabetes, Science, 2006, vol. 313, no. 5790, pp. 1137–1140.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Peng, L., Li, Z.R., Green, R.S., Holzman, I.R., and Lin, J., Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers, J. Nutr., 2009, vol. 139, no. 9, pp. 1619–1625.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Perrini, S., Natalicchio, A., Laviola, L., Belsanti, G., Montrone, C., Cignarelli, A., et al., Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane, Diabetes, 2004, vol. 53, pp. 41–52.CrossRefPubMedGoogle Scholar
  34. Roach, W. and Plomann, M., PACSIN3 overexpression increases adipocyte glucose transport through GLUT1, Biochem. Biophys. Res. Commun., 2007, vol. 355, no. 3, pp. 745–750.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Satoh, N., Naruse, M., Usui, T., Tagami, T., Suganami, T., Yamada, K., et al., Leptin-to-adiponectin ratio as a potential atherogenic index in obese type 2 diabetic patients, Diabetes Care, 2004, vol. 27, no. 10, pp. 2488–2490.CrossRefPubMedGoogle Scholar
  36. Savage, D.B., Petersen, K.F., and Shulman, G.I., Mechanisms of insulin resistance in humans and possible links with inflammation, Hypertension, 2005, vol. 45, no. 5, pp. 828–833.CrossRefPubMedGoogle Scholar
  37. Shang, W., Yang, Y., Zhou, L., Jiang, B., Jin, H., and Chen, M., Ginsenoside Rb1 stimulates glucose uptake through insulin-like signaling pathway in 3T3-L1 adipocytes, J. Endocrinol., 2008, vol. 198, 561–569.CrossRefPubMedGoogle Scholar
  38. Taniguchi, C.M., Emanuelli, B., and Kahn, C.R., Critical nodes in signalling pathways: insights into insulin action, Nat. Rev. Mol. Cell. Biol., 2006, vol. 7, no. 2, pp. 85–96.CrossRefPubMedGoogle Scholar
  39. Vangipuram, S.D., Yu, M., Tian, J., Stanhope, K.L., Pasarica, M., Havel, P.J., et al., Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells, Int. J. Obes. (Lond.), 2007, vol. 31, no. 1, pp. 87–96.CrossRefGoogle Scholar
  40. Vega, G.L. and Grundy, S.M., Metabolic risk susceptibility in men is partially related to adiponectin/leptin ratio, J. Obes., 2013, vol. 2013, p. 409679.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • H. Fakhoury
    • 1
  • S. Osman
    • 1
  • N. Ghazale
    • 2
  • N. Dahdah
    • 1
  • M. El-Sibai
    • 2
  • A. Kanaan
    • 1
    Email author
  1. 1.Department of Biomedical Sciences, Faculty of Medicine and Medical SciencesUniversity of BalamandEl-KurahLebanon
  2. 2.Department of Natural Sciences, School of Arts and SciencesLebanese American UniversityBeirutLebanon

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